CS227038B2 - Method of preparing ammonium salts of substituted carboxylic acid - Google Patents

Description

The invention relates to a process for the preparation of ammonium salts of a substituted carboxylic acid of the formula I

in which

R 1 represents a tri- (hydroxymethyl) methyl group and

R 2 and R 5 are hydrogen, or both R 1 and R 2 are each ethyl, 2-hydroxyethyl or 2-hydroxypropyl; and

R 3 is hydrogen, or

R 1 and R 2 together represent a 3-oxa-1,5-pentylene group and

R 5 is hydrogen, or

R 1 represents a 2,3,4,5,6-pentahydroxy-n-hexyl group,

R2 is methyl and

R 3 is hydrogen, or

R 1, R 2 and R 3 are 2-hydroxyethyl, which have valuable pharmacological properties and can be used as drug active ingredients.

The 2- (2,6-dichloroanilino) phenylacetic acid (Diclofetnac) which is the base of the salts of the formula I as well as its salts, in particular its salts with bases, are known compounds.

The respective sodium salt is used as a non-steroidal antiinflammatory agent in the treatment of inflammatory processes. The corresponding pharmaceutical preparations are usually administered enterally, such as orally or rectally, and then parenterally.

However, known formulations containing the sodium salt of 2- (2,6-dichloroanilino) phenylacetic acid are, for various reasons, unable to fully satisfy the requirements. Thus, especially when administered orally, side effects can be observed, particularly in the gastrointestinal area, such as ulceration of gastric and intestinal mucosa. tract.

When parenterally administered, the relatively low solubility of 2- (2,6-dichloroanilino) phenylacetic acid sodium salt in water is disturbing. This disadvantage is particularly evident in the case of injection solutions intended for intramuscular administration. Relatively large amounts of fluid are required, which often entails unpleasant local irritation.

In addition, the sodium salt of 2- (2,6-diohoranilino) phenylacetic acid is difficult to process into locally applicable dosage forms.

These disadvantages of 2- (2,6-dichloroanilino) phenylacetic acid sodium salt pharmaceutical formulations can be overcome or at least substantially reduced by the use of the novel salts of formula I. Thus, the salts produced by the process of the invention are better tolerated in the gastrointestinal tract and water is much more soluble than the sodium salt of 2- _(2-1 6 dlchloraniiinojfenyloctové acids. the novel salts of formula I possess all the desirable pharmacological properties of the disclosed compounds then at least to an equivalent degree of effect, but they are based on their specific advantages such as significantly more acceptable for enteral, especially oral and one for. parenteral and topical administration. thus, a particular salt of a Formula I wherein Ri is 2,3,4,5,6-pentahydroxy-n ^ ^h exylovou with full ^ ^R 2 is methyl and R3 is hydrogen, especially 2- (2,6-dichloroanilino) phenylacetic acid salt of 1-deoxy-1- (N-methyl-D-glucamine or Meglumine), followed by a salt of formula I wherein R 1 and R 2 are ethyl and R 3 is. Hydrogen, the excellent antiinflamatory and analgesic properties and compared to the sodium salt of 2- (2,6 чИсЫогапШпо) phenylacetic acid, is better tolerated by the gastrointestinal tract and moreover, it has a substantially better - for example triple - solubility in water.

Antiinflammatory efficacy can be demonstrated, for example, by a marked reduction in edema in the edema test on a carragen-induced rat paw in a dosage range of from about 1 to about 10 mg / kg po while an analgesic effect can be demonstrated for example, by the phenyl-p-benzoquinone-induced pain test [J. Pharmaool. Exptl. Therap., Vol. 125, p. 237 (1959)] at a dosage range of from about 2 to about 20 mg / kg p.o.

To demonstrate better gastnointestinal compatibility, the following test arrangements are suitable, among other things: rats (per dose of 5 males and females of 220 to 280 g each) are administered orally 21 and 6 hours prior to autopsy using a stomach tube. · Preparation. The gastric mucosa is then examined for ulcers, and the number and severity is evaluated using an index of 0 to 14. The proportion of infected animals is then determined. The dose of the test product that causes the ulcer disease evaluated by index 3, if appropriate by interpolation, is determined as a measure of the presence of gassrointestinal ulceration.

Comparative trials of gastrointestinal tolerability in groups of 10 test animals (rats) after two oral doses of 10 mg / kg each show a gastric damage rate of 60% of the treated animals for the sodium salt of 2- (2,6-dichloroanone) phenylacetic acid and for the salt 2- (2,6-dichloroanilino) phenylacetic acid with 1-deoxy-1-methylmethylamino) -D-glucite corresponding to the injury rate in 30% of treated animals.

Further, for the sodium (2- (2,6-dichloroanilino) phenylacetic acid) sodium salt in the Ulcus Index test, also after oral administration twice to 10 mg / kg groups of 10 test animals, the Ulcus index was found to be 6.6 compared to 5.0 for the corresponding 1-deoxy-1- (methylamino) -D-glucite salt.

The "Ulcus-index" refers to the number and extent of gastric damage in experimental animals. From these test results. it can be clearly established that the ammonium salts of 2- (2,6-bis-phenylacetic) phenylacetic acid are, for example, significantly better tolerated by the gastric mucosa compared to the corresponding alkali metal salts, both in number and type of damage. · ..

Salts of formula (I), and in particular a preferred salt of 2- (phenylacetate). Acids ·. with 1-deoxy-1- (methylamino) -D-glucite, as well as the corresponding diethylammonium salt, are therefore useful as antiinflammatory and analgesic agents, in particular for oral or parenteral administration and also for topical application.

Accordingly, the present invention provides a process for the preparation of the novel salts of formula (I), which is characterized in that it is mentioned in U.S. Pat. by reacting 2- (2,6-dichloroanilino) phenylacetic acid or a salt thereof which differs from the salt of formula I with a base with an amine of formula II

R 1 -N (R 2) -R 3 '(II) wherein

R 1, R 2 and R 3 have the above meanings, or with an acid addition salt thereof.

The bases which can be used as starting materials are salts of 2- (2,6-dichloroannino) phenylacetic acid, for example, metal salts, for example alkali metal salts and alkaline earth metal salts, such as sodium, potassium or calcium salts, preferably those whose basic components, which form a sparingly soluble salt in the reaction medium with the acid addition salt component of the amines of formula II.

Salts of amines of the formula II are, for example, salts with acids which are readily removable from the reaction mixture or which, with the basic component, the salts of 2- (2,6-011- 8-^) phenylacetic acid used as a starting material, forms a sparingly soluble salt. They are salts with volatile acids or with acids which are less acidic than 2- (2,6-dichloroano) phenylacetic acid, such as salts with inorganic acids, for example salts with hydrohalic acid or sulfuric acid. or with volatile carboxylic acids, further with mono- or dithlokarboxylic acids, for example lower alkanoic acids, carbonic acid or dithiocarbonic acid, and 1 with their semi-esters and semi-amides, such as the corresponding acetates, carbonates, bicarbonates, carbamates, dithiocarbamates or (lower) jaikoxyformiáty.

The reaction is preferably carried out in the presence of an inert solvent or diluent, using, for example, alcohols such as lower alkanols such as methanol or ethanol, ethers such as di (lower) alkyl ethers such as diethyl ether, cyclic ethers such as dioxane or tetrahydrofuran, ketones such as di (lower) alkyl ketones, for example acetone, carboxylic acid esters, such as lower alkyl esters of lower alkanecarboxylic acids, for example ethyl acetate, amides such as N, N-di (lower) alkyl amides of lower alkanecarboxylic acids, for example N, N-dimethylformamide, sulf oxides such as dl (lower alkylsulfoxides, for example dlmethylsulfoxides or water or mixtures thereof. Optionally, cooling and heating are performed, for example, in a temperature range of from about 0 ° C to about 100 ° C in a closed vessel and / or an inert gas atmosphere such as nitrogen. .

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

The salts of the formula I can be used as medicaments, in particular as antlinflamatorics and analgesics. The dose of the active ingredient depends on the species, age and individual condition as well as the mode of administration. Usually, it is used for warm-blooded weight of about 70 kg by enteral or parenteral administration of an approximate daily dose of. about 75 to about 250 mg, optionally divided into multiple doses.

The pharmaceutical preparations containing the salts of the formula I are pharmaceutical preparations for enteral, such as oral or rectal, and / or parenteral administration, as well as for topical administration, these preparations containing the active substance alone or containing the active substance together with a pharmaceutically acceptable carrier.

The novel pharmaceutical preparations are, for example, unit dose pharmaceutical preparations such as preparations for oral administration, for example dragees, tablets and capsules, preparations for rectal administration, for example suppositories or preparations for parenteral administration, which are customary in the form of ampoules. Formulations for oral administration contain, for example, from about 10 to about 80, preferably from about 20 to about 50% by weight, non-aqueous injectable solutions, for example from about 0.5 to about 10, preferably from about 0.5 to about 5% by volume, and aqueous injectable solutions, for example, from about 0.3, preferably from about 0.5% by volume to saturation of the active ingredient. ’

Pharmaceutical preparations useful for oral administration may be prepared in a manner known per se, for example by means of conventional mixing, granulating and draining processes.

Thus, for example, the active ingredient may be combined with solid carriers, the resulting mixture optionally being granulated, and the mixture or granulate, if desired or necessary, after the addition of additional excipients, processed into tablets or dragee cores.

Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or middle calcium phosphate, binders such as greasy starch using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrating agents such as the aforementioned starches, further carboxymethylated starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or salts thereof such as sodium alginate. The auxiliaries are in particular flow control agents and glidants, for example silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate and / or polyethylene glycol.

Dragee cores may be provided with suitable coatings, optionally resistant to gastric acid, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in a suitable organic. solvents or solvent mixtures, or for producing gastric acid-resistant coatings, solutions of suitable cellulosic preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyestuffs or pigments may be added to the tablets or to the coated dragee cores, for example to identify or distinguish different doses of the active ingredient.

Other pharmaceutical preparations useful for oral administration are push-fit capsules of gelatin as well as soft, sealed capsules of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers may also be added.

Suitable pharmaceutical preparations for rectal administration are, for example, suppositories which consist of a combination of the active ingredient with a suppository base. Suitable base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols, and mixtures thereof. In addition, rectal gelatin capsules can be used which contain a combination of the active ingredient with a matrix. Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

For parenteral administration, especially aqueous solutions, suspensions of the active ingredient, as the corresponding oily injection suspensions, are suitable, and suitable lipophilic solvents or media such as fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides may be used, or aqueous injectable suspensions which may contain viscosity enhancers, for example sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally also stabilizers.

As topical pharmaceutical preparations; especially suitable are creams, ointments, pastes, foams, elixirs and solutions which contain from about 0.5 to about 10%, such as from about ... 0.5 to about 5% of the active ingredient.

Creams are represented by oil-in-water emulsions containing more than 50% water. Fatty alcohols, for example lauryl alcohol, are preferably used as oily bases. cetyl alcohol - or stearyl alcohol, fatty. acids such as palmitic acid or an acid. stearic, liquid to solid waxes, for example isopropyl myristate, sheep 's wax or. beeswax and / or hydrocarbons such as petrolatum or paraffin oil. Suitable emulsifiers are surfactants having predominantly hydrophilic properties, such as the corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or their adducts with ethylene oxide, such as fatty acid esters of pplyglycerol, or fatty acid ethers. polyoxyethylene sorbitan (Tweens) or polyoxyethylene fatty alcohol ethers or polyoxyethylene fatty acid esters, as well as corresponding ionic emulsifiers such as alkali metal sulfated fatty alcohol salts, for example sodium lauryl sulfate, sodium acetate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, e.g. The additives to the aqueous phase are, inter alia, agents which prevent the drying of the cream, such as polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols; preservatives, fragrances, etc.

Ointments are water-in-oil emulsions containing up to 70%, but preferably from about 20% to about 50%, of water or an aqueous phase. Suitable fatty phases are, in particular, hydrocarbons, for example petrolatum, paraffin oil and / or hard paraffin, furthermore suitable hydroxyl compounds, such as fatty alcohols or their esters, for example cetyl alcohol or wool wax alcohols or sheep wool wax. The emulsifiers are represented by appropriate lipophilic substances such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and / or sorbitan isostearate. Additives to the aqueous phase are, inter alia, moisture-retaining agents, such as polyalcohols, for example glycerol-1, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.

Fatty ointments are anhydrous and contain, in particular, hydrocarbons such as paraffin, petrolatum and / or liquid paraffins, natural or partially synthetic fats such as coconut oil fatty acid triglyceride, or preferably hardened oils such as hydrogenated peanut oil or castor oil; glycerol fatty acid esters, for example glycerol mono- and di-stearate, as well as, for example, fatty alcohols, emulsifiers and / or water-intake additives mentioned in connection with ointments.

Pastes are creams and ointments with a powder constituent capable of absorbing secretions, such as metal oxides, for example titanium dioxide or zinc oxide, talc or aluminum silicates, which are intended to bind the moisture or secretions present.

The foams are applied from pressurized containers and are represented by liquid oil-in-water emulsions present in aerosol form using halogenated hydrocarbons such as propellant. chloro fluoro (lower) alkanes, for example dichlorodifluoromethane and dichlorotetrafluoroethane. The oily phase used is, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and / or other waxes. Mixtures of emulsifiers with predominantly hydrophilic properties such as fatty acid esters and polyoxyethylene sorbitan (Tweens) and emulsifiers with predominantly lipophilic properties such as sorbitan fatty acid esters (Spans) are used as emulsifiers. In addition, conventional additives such as preservatives, etc. are added.

Tinctures and solutions usually contain an aqueous-ethanolic base to which, inter alia, polyalcohols such as glycerol, glycols and / or polyethylene glycol may be added as moisture retardants to reduce evaporation and fat retardants such as fatty acid esters of lower polyethylene glycols , i.e., lipophilic substances which are soluble in the aqueous composition, as a substitute for fatty substances removed from the skin with ethanol, and optionally other excipients and additives.

Topical pharmaceutical preparations are prepared in a manner known per se, for example by dissolving or suspending the active substance in the base substance or part thereof, if necessary. When the active substance is applied in the form of a solution, it usually dissolves in one of the two phases before emulsification. When processed as a suspension, the active ingredient is mixed with a portion of the base after emulsification and then added to the remainder of the formulation.

The following examples illustrate the invention described above. However, these examples are not intended to limit the scope of the invention in any way. Temperatures are given in degrees Celsius.

Example 1

A suspension of 6.64 g of 1-deoxy-1-methylmethylamino) -D-acetate 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. for 16 hours. After 2 hours, white, fine crystals precipitated. Then the solvent was removed under reduced pressure and the white, sticky residue was dissolved in a small amount of hot water. The clear solution was then allowed to slowly cool to 0 ° C and allowed to stand at this temperature for 16 hours. An oily, semicrystalline mass is formed which is filtered off over diatomaceous earth and cloth filter over a period of 2 days. The filter residue is dried at 100 ° C / 1 mmHg for 1 week and then sprayed. The 2- (2,6-dlchloroanilino) phenylacetic acid salt of 1-deoxy-1- (methylamino) -D-glucite melts at 127-137 ^° C.

Example 2,

10.0 g of 2- (2,6 - ^ <^ i <^ l ^] ^ i ^ ^ U ^ Iraj no]: ^ € ^ y ^ y ^r ^ c ^ c ^ 1 c ^ v ^ s acid - dissolved with stirring in 230 ml of ethyl acetate, 6.64 g of 1-deoxy-1- (methylamino) -D-glucite are added thereto, and the reaction mixture is left to stir for 16 hours. It is washed with a small amount of ethyl acetate and dried at 60 DEG C. under reduced pressure, the crude product is treated with 600 ml of hot isopropanol and the insoluble material is filtered off, and the filtrate is concentrated to a volume of about 500 ml. After 3 hours, the reaction mixture is stirred under ice-cooling at room temperature, the reaction mixture is filtered again, the residue on the filter is washed with cold isopropanol and the precipitate is dried at 60 ° C under reduced pressure to a constant weight. 2,6-dichloroanilino-phenyl acetic acid with 1-deoxy-1- (methylamino) -D-glucite, m.p. 142.5-145 ° C.

Example 3

To a solution of 2 g of 2- (2,6-dichloroanilino) phenylacetic acid in 40 ml of diethyl ether is added 2 ml of diethylamip. The solution was heated at reflux for 10 minutes, then cooled and concentrated under reduced pressure, whereupon diethylammonium 2- (2,6-dichloroanilino) phenylacetate crystallized out. The colorless crystals were filtered off and dried under high vacuum at room temperature. Melting point 110-115 ° C (decomposition).

Example 4

4.53 g of tri- (hydroxymethymethylamine) dissolved in 10 ml of water are added dropwise over 10 minutes to a solution of 10 g of 2- (2,6-dichloro-phenylacetic acid) in 230 ml of ethyl acetate at room temperature and with vigorous stirring, immediately precipitating the salt. The mixture was stirred at room temperature for half an hour and the solvent was removed under reduced pressure. The white crystalline residue was dissolved at about 50 ° C in 1000 ml of a 1: 1 mixture of acetone and water. The solution was allowed to crystallize at 0 DEG C. The precipitated white flaky crystals were filtered off and dried under high vacuum to give the tri- (hydroxymethyl) methyl ammonium 2- Phenylation melting of (2,6-1сЫота1Шшо) melts at 202 to 204 ^° C.

Example 5

5.52 g of tri- (2-hydroxyethyl) amine ¹ ' are added dropwise over 10 minutes to a solution of 10 g of 2- (2,6-methyl-1,1-dimethyl-acetic acid in 230 ml of ethyl acetate at room temperature with vigorous stirring). dissolved in 30 ml of ethyl acetate, the salt precipitated immediately, and the mixture was stirred for a further half an hour at room temperature and the solvent was removed under reduced pressure, the white crystalline residue was dissolved in a small amount of hot ethanol. The solution was allowed to crystallize at 0 DEG C. The white crystals were filtered off and dried under high vacuum to give the tri (2-hydroxyphenyl) ammonium-2 melting at 137 DEG-138 DEG.

Example 6

To a solution of 10 g of 2- (2,6-dichloroanilino) phenylacetic acid in 230 ml of ethyl acetate at room temperature with vigorous stirring was added dropwise over 10 minutes 3.89 g of di- (2-hydroxyethyl) amine suspended in 30 ml. The resulting salt is immediately precipitated, the mixture is stirred for a further half hour at room temperature and the solvent is removed under reduced pressure, Na227038 the yellow, crystalline residue is dissolved in a small amount of boiling ethanol. di- (2-hydroxyethyl) ammonium-2- (2,6-dichloroanilinophenylacetate) crystallized, melting at 130-132 ° C.

Example 7

To a solution of 10 g of 2- (2,6-dichloroanilino) phenylacetic acid in 230 ml of ethyl acetate, 3.22 g of morpholine in 30 ml of ethyl acetate was added dropwise over 10 minutes at room temperature with vigorous stirring. About 10 minutes after the addition of morpholine, the salt precipitates. Then the mixture was further stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. Then, the white, crystalline residue is dissolved in boiling ethanol. At 0 ° C, morpholinium 2- (2,6-dichloroanilino) phenylacphthate crystallizes, melting at 162-165 ° C.

Example

To a solution of 10 g of 2- (2,6-dichloroanilino) phenylacetic acid in 230 ml of ethyl acetate, 4.93 g of di-2-hydroxypropyl iamine in 30 ml of ethyl acetate was added dropwise over 5 minutes at room temperature with vigorous stirring. After a short time the salt precipitated. The mixture was stirred for 1 hr, earth and solvent was removed under reduced pressure and the white crystalline precipitate was dissolved in a 'small amount of hot ethanol and allowed to stand at 0 ^e C, the crystallized di- (2-hydroxypr.o> yl) amonium- 165 DEG-170 DEG C. 2- (2,6-bis-phenyl) -phenylacetate.

... 7

Example 9

Tablets containing 75 mg of the salt of 2- (2,6-dichloroamino) phenylacetic acid with 1-deoxyxyl- (methylamino) -D-glucitin may be prepared as follows:

Ingredients (for · 10,000 tablets):

2- (2,6-dichloroanilino] phenylacetic acid salt with 1-deoxy-1- (methylamino) -D-glucate 750.0 g lactose (ground) 350.0 g polyvinylpyrrolidone (PVP K 30 PH) 50.0 g colloidal silica (Aerasil <R) 200) 30.0 g microcrystalline cellulose (Avicel (R ⁾ PH 102) 400.0 g corn starch 690.0 g magnesium stearate 3p, 0 g water as needed

The active ingredient is mixed with lactose and the mixture is granulated with an aqueous solution of polyvinylpyrrolidine. The wet mixture is dried, ground and mixed with other excipients within 10 minutes, and the tablets are then compressed into tablets (9 mm diameter; weight 230 mg).

Example 10

Capsules containing 25 mg of a salt of 2- (2,6-dichloro-4-amino) phenyl acetic acid with 1-deoxy-1- [methylamino] glucan can be prepared, for example, as follows:

Composition (for 10 000 capsN):

2- (2,6-dichloroanilino) phenylacetic acid salt with 1-deoxy-1- (methylamino) -D-glucit 225.0 g milk sugar 445.0 g magnesium stearate salt 5.0 g

The ingredients were blended in a suitable blender, sieved (# 40), blended again, and 75 mg each filled into gelatin capsules of appropriate size.

Example 11

Injectable solutions containing 2% by weight of 2- (2,6-dichloroanilino) -phenylacetic acid salt of 1-dioxoxy-1- (methylthylamine) glucite may be prepared, for example, according to either of the following two methods:

Example 11a

Composition (for 1 ml of solution):

2- (2,6-dichloroanapo) -phenylacetic acid salt with 1-deoxy-1- (methylamino) -D-glucite 20 mg marniitol (pyrogen-free) 6 mg water for injections up to 1 ml

The mannitol and the active compound are dissolved in about 90% of the prescribed amount of water under stirring and under a nitrogen atmosphere. After complete dissolution, make up to volume with water. The solution for injection is sterile filtered through a membrane filter (pore size á 0.22 μπι) and then filled into sterilized glass ampoules under a nitrogen atmosphere and sealed under a nitrogen atmosphere. The sealed vials are heated at 120 ° C for 20 minutes in an autoclave.

Example 1b 11b

Composition (for 1 ml of solution):

2- (2,6-dilhl.lα ^, aniiino phenyl) acetic acid salt with 1-deoxy-1-

- (methylamino) -D-glucite 20 mg be ^ y ^ who! 40 mg 1,2-propylene glycol 200 mg water for injection purposes to 1 ml Mannitol,, benzylalkhal and 1,2-p ropene- the glycol was under a nitrogen atmosphere dissolve

in about 70% of the prescribed amount of water. The active ingredient was added to the solution and the mixture was stirred until complete dissolution and then diluted to final volume with water. The solution for injection is sterile filtered through a membrane filter (pore size: ≥ 0.22 µm) and then filled into a nitrogen atmosphere. sterilized glass ampoules, and these are sealed under a nitrogen atmosphere. The sealed ampoules are heated at 120 ° C for 20 minutes in an autoclave.

Example 12. . A cream containing 5% dimethylammonium-2- (2,6-dlchloranillin-phenylacetate) can be prepared as follows:

Ingredients:

diethylammonium 2- (2,6-dichloro-amino) isoyl acetate 5% mono and diglycerides of higher saturated fatty acids with potassium stearic acid (self-emulsifiable glycerin monostearate) 17% oleic acid decyl ester 5% propylene glycol 20% water, demineralized to 100 %

The active ingredient is dissolved in propylene glycol and water. The self-emulsifiable glycerin monostearate is melted together with the oleic acid decyl ester. The aqueous phase is then added to the fatty phase and emulsified. Optionally. fragrance (0.1%) is added. .. ·. ··. .; ·

13, &quot; Ointment containing &quot; 5% of dimethylammonium 2- (2,6-dichloro-phenoxy) phenylacetate can be prepared as follows: .....

'. Composed by. .., _;

У,'У diethylammonium-2- (2,6-dichloro-γ-aniline) acetate 5% • УТУ propylene glycol У 12% white petrolatum 28% microcrystalline wax 2% fatty acid sorbitan ester 25% water, demineralized to 100%

The active ingredient is dissolved in propylene glycol and water. Fatty substances, ie petrolatum, wax. and the sorbitan fatty acid ester is melted together. Thereafter, the active ingredient solution is emulsified in the fatty phase and fragrances (0.1%) are optionally added.

Example 14

A transparent hydrogel containing 5% dimethylammonium-2- (2,6-dlchloro) phenylacetate can be prepared as follows:

Ingredients:

diethylammonium-2- (2,6-dichloroanilino) phenylacetate 5% propylene glycol 20% isopropanol 20% acrylic acid polymer 2% tri-2-hydroxyethyl iamine 3% water to 100%

The polymer / acrylic acid and water are dispersed and the dispersion is neutralized with tri- (2-hydroxyethyl) amine. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. Thereafter, a solution of the active ingredient is mixed with the gel, optionally with fragrance (0.1%) added.

Example 15

A cream containing 5% of 2- (2,6-dichloroanilino) pyrrolidinyl-1-deoxy-1- (methylamino) -D-glucite salt can be prepared as follows:

Ingredients:

2- (2,6-dichloro-loganino) -phenylacetic acid salt with 1-dieoxy-1- (methylamino) -D-gluconate 5% of higher-saturated mono- and diglycerides. . . priced fatty acids with expensive stearic acid salt (self-emulsifiable glycerin / monostearate) 17% oleic acid decyl ester 5% propylene glycol 20% water, demineralized to 100%

This cream is produced by the method described in Example 12.

EXAMPLE 16 g of 2- (2,6-dichloroanilino) phenylacetic acid sodium salt are dissolved in 100 ml of ethanol at room temperature and 1.72 g of diethylammonium hydrochloride are added to the solution, which immediately precipitates a crystalline product. The reaction mixture was stirred at room temperature for 1 hour and then filtered through a filter aid. The filtrate is concentrated to dryness. 40 ml of ethyl acetate / ether (1: 1) was added to the crystalline residue and the mixture was filtered. The white crystalline residue on the filter was washed again with 20 ml of ethyl acetate / ether and dried under high vacuum. It is obtained. diethylammonium salt of 2- (2,6-dichloroanilino) phenylacetic acid, m.p. 131-140 ° C.

AND

Claims (9)

Subject What is claimed is: 1. A process for the preparation of a substituted carboxylic acid arnonyl salt of the general formula I wherein * R1 is tri- (hydroxymethyl) methyl and; R 2 and R 3 are hydrogen, or both R 1 and R 2 are each an ethyl 'group' 2-hydroxyethyl or 2-hydroxypropyl; and R 3 is hydrogen, or R1 and R2 together represent a 3-oxa-1,5-pentylene group and R 3 is hydrogen, or R 1 is a hydroxy-n-hexyl group; :. . R 2 is methyl and R 5 is hydrogen, or. · '. ··· R ⁵ · Ri, R2 and R3 are 2-hydroxyethyl group, characterized in that the · 2- (2,6 <lichlorainiinojfenyloctovou acid ^'1' or a salt thereof, which is different from the salt of the formula · Ί with a base with an amine of formula II i j _'you / i;. ·. -II' V 'j · R-N (R) L j-R3 (II) wherein .....' of 7 R 1, R 2 and R 3 have the meanings given above, or an acid addition salt thereof. , 2.. The process of claim 1 wherein the 2- (2,6-dichloroanino) phenylacetic acid is treated with an amine of formula II. 3. A process according to claim 1 or 2, for the preparation of diethylammonium 2- (2,6-dicloroalino) phenylacetate, characterized in that 2- (2,1-dihydroxy) -phenylacetate is used as starting material. 1 (N, N, N-phenylacetic acid and diethylamine). 4. Process according to claim 1 or 2, for the preparation of salts of 2- (2,6-dichloroanilino) phthylacetic acid with 1-deoxy-1- (methylamino-D-glucite), characterized in that 2- (2,6-dichloroanilino) phenylacetic acid and 1-deoxy-1- (methylamino) -D-glucate. 5. A process according to claim 1 or 2, for the preparation of tri- (hydroxymethyl) methylammonium 2- (2,6-dlchloroanilino) phenylacetate, characterized in that 2- (2,6-dichloroanilino) phenylmethanoic acid and tri (III) are used as starting materials. - (hydroxymethyl) methylamine. 6. The process according to claim 1 or 2, for the preparation of tri (2-hydroxyethylammonium-2- (2,6-dichloroanilino) -itenylacetate, characterized in that 2- (2,6-dichloroanilino) tenylacetic acid is used as starting material and tri- (2-hydroxyethyl) amine. 7. A process according to claim 1 or 2 for the preparation of dl- (2-hydroxyethyl) ammonium 2- (2,6-dichloroanilino) phenyl acetate, characterized in that the starting materials used are: 2- (2,6-dlchlorolanino-phenylacetic acid) and dl- (2-hydroxyethyl) -amine. 8. Process according to claim 1 or 2, for the preparation of morpholinium-2- (2,6-dichloroanilino) phenylacetate, characterized in that 2- (2,6-dichloroinilino) phthnylacetic acid and morpholine are used as starting materials. .;; < 9. A process according to claim 1 or 2, for the preparation of dl- (2-hydroxy-propyl) -ammonium-2- (2,6- > -dichloroanilino), characterized in that 2- (2, 2 &apos; 6 dichloranlll ^ n ^ o) ft ^ NYO ^ ^{(^,} ^ c ^ \ ^ · E · acid and di- (2-hydroxypropyl) amine. Severografla, n. P., Plant 7, Most Price £ 2.40 s