DE2317579A1 - SALTS OF 2,6-DIOXOCYCLOHEXANTHIOCARBONIC ACID 4'-HALOGENANILIDES AND THEIR PHARMACEUTICAL PREPARATIONS - Google Patents

Description

FARBWERKE HOECHST AG formerly Meicter Lucius & Brüning ^ 1 File number: hoe 73 / F 097

Date: March 26, 1973 Dr. D / stl

Salts of 2, ö-Dioxocyclohexanthiocarbonsäure- ¹ ! '-Haloanilides and their pharmaceutical preparations

For the past 10 to 15 years, skin fungal infections have contributed Domestic animals and farm animals are gaining increasing economic importance. In addition, infected animals are not just a reservoir for the infection of other animals, but are also a considerable due to the close coexistence of humans and animals Source of infection for humans.

This development is favored by the massing of large numbers of animals in a small space, which leads to intensive contact the animals come among each other. This generally increases the risk of infection considerably enlarged. Furthermore, dogs and cats are also kept in non-agricultural households or other luxury animals experienced a significant upswing. However, it is precisely these animal species that are often affected by skin fungal infections, and the question of suitable preparations for therapy is made more and more urgent by the small animal practice. While with the farm animals as the main one Trichophyton species of the skin fungus occur, in addition to these, it is mainly microsporon species in the small pets.

In recent years there has therefore been no lack of efforts to develop a skin fungus preparation that can be used in all domestic and farm animals can be used and with its spectrum of activity covers the most important skin fungi occurring in veterinary medicine.

Local and spray applications are particularly suitable for application andv / final preparations. In addition to good skin tolerance and good; Adhesion, these preparations must be able to

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the keratin to penetrate the skin and hair to get to the The seat of the infectious agent. Despite the good antiraykotic effect proven in vitro, with many remedies do not achieve satisfactory treatment results.

The poorly water-soluble dioxocyclohexanecarboxylic acid anilides described in German Offenlegungsschrift No. 2 039 466 have excellent antimycotic properties. For example, 2,6-dioxocyclohexanecarboxylic acid-4'-bromanilide, dissolved 1 % in diethyl carbonate, was used to treat 6 fattening bulls with moderate to severe trichophytosis. The treatment was carried out in such a way that the preparation solution was applied to the diseased skin areas twice with an interval of 3 days using a cotton ball.

It was found that the trichophytic disease treated in all 6 Bulls healed completely within 20 to 25 days of starting treatment. In a follow-up period of more than 6 weeks there were no recurrences. The skin fungal infection of the animal treated only with diethyl carbonate and the 4 untreated animals Controls showed a clinically unchanged picture during this time.

Despite their good effectiveness, these compounds are less suitable for use in veterinary medicine. You own Solubility sufficient for therapeutic purposes only in organic solvents. The handling of such solutions is often not harmless (risk of explosion, fire, etc.).

The use of medicinal products in veterinary medicine, in particular, if the application is not carried out by the veterinarian, however, a simple application method is required. As a preparation form suitable for a veterinary skin fungus preparation Particularly dry preparations that are good in tap water are soluble.

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Alkali or alkaline earth salts of 2,6-Dioxocyclohexanearbonsäure- ^ ' However, haloanilides show insufficient water solubility for therapeutic purposes and are moreover aqueous Solution only stable at pH> 12.

It has now been found that by dissolving alkali or alkaline earth salts of 2,6-dioxocyclohexanthiocarboxylic acid V-haloanilides of the general formula I.

0 ^θ Me® £ / ^NH - (7

C NH-A \ _X

o \ A = /

Me I

where X is halogen and Me is an alkali or alkaline earth metal _} in water, stable and odorless solutions are obtained.

The subject of the invention are therefore physiologically compatible Alkali and alkaline earth salts of 2, o-dioxocyclohexane-thiocarboxylic acid-M'-haloanilides of the formula I, processes for their production and preparations which contain them as active ingredients.

Those compounds in which X is chlorine are particularly preferred.

The salts are prepared by reacting 2,6-dioxocyclohexanthiocarboxylic acid-iP-haloanilide with an (earth) alkali hydroxide bicarbonate or alcoholate.

The reaction is preferably based on equivalent amounts of the two starting compounds. With an excess of acid an impure product is obtained because the unreacted acid precipitates with the salt. On the other hand, an excess of base does not bother since this remains dissolved in the mother liquor when the salt is separated off

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When using the alkali metal or alkaline earth metal hydroxides or bicarbonates can be as solvent, water, lower alcohols _s (C. -C ^) aqueous lower alcohols (C ₁ -C, -), using, aqueous tetrahydrofuran, aqueous dioxane or aqueous acetone. When using the alkali or alkaline earth alcohols, anhydrous lower alcohols (C, -C ^) or anhydrous inert solvents are used. The procedure is that a solution of an alkali or alkaline earth metal hydroxide or a solution or suspension of an alkali or alkaline earth metal alcoholate is prepared and it is reacted with 2,6-dioxo-cyclohexanthiocarboxylic acid- ^ '-halogenanilide. The salts of 2,6-dioxocyclohexanthiocarboxylic acid - ^ '- halogenanilids were obtained from their solutions by crystallization, concentration until crystallization or by precipitation after addition of suitable solvents such as acetone.

The acids suitable as starting compounds are obtained, for example, in accordance with the information in DOS 2 039

The preparations according to the invention are preferably dry preparations from which a therapeutically applicable solution is prepared by dissolving in tap water. The active ingredient content of these solutions is preferably approximately 1 %.

Since the alkaline earth salts of 2,6-dioxocyclohexanthiocarboxylic acid ⁱ l'-haloanilides are less water-soluble, it is advisable to add a complexing agent to this dry preparation in order to ensure a therapeutically effective concentration of the active ingredient in the aqueous solution. The addition of a complexing agent is also necessary if the dry preparation contains an alkali salt, since the alkaline earth metal ions which may be present in tap water would create and precipitate the less water-soluble alkaline earth metal salts during the preparation of the aqueous solution.

Because of the poor flowability of the salts, the trophy preparations contain the active ingredient and the complexing agent water-soluble auxiliaries such as 2.B. Polyglycols.

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The compounds according to the invention show in in vitro tests sees good inhibiting action against Trichophyton spp and Microsporon ssp

This result has also been confirmed in veterinary practice.

The (earth) alkali salts of 2,6-Dioxocyclohexanthiocarbonsäure- * were used for therapy attempts! '-chloranilids in the form of a tap water-soluble dry preparation, the potassium carbonate, Polyglycol 4000 and tetrasodium edetate (tetrasodium salt of Ethylenediamine tetraacetic acid) had been added as auxiliary substances. The solutions came 1> Sig, based on the active ingredient, to use.

Treatment of a total of I87 cattle with a naturally acquired one Trichophytic infestation had the following result:

all in all cured with ... improved little not treated treatments better cured

Ix 2x 3x Hx 6x
187 H '84 39 12 5 5 23 ⁺⁾ 15

+) For 21 cattle the observation time was only 17 days after the 2nd treatment

Treatment successes on dogs and cats showed that the invention The salts produced are also used for the therapy of Microsporon canis and trichophytic diseases in these animal species can be.

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example 1

Sodium salt of 2,6-dioxocyclohexanethiocarboxylic acid 4'-chloroanilide

In a solution of 9.0 g of pure sodium hydroxide in 68O ml of water, 60 g of 2,6-dioxocyclohexanethiocarboxylic acid ⁱ l'-chloroanilide are introduced with stirring. It is stirred for 15 minutes after, the solution is filtered and evaporated in vacuo at 50 ⁰ C to a small volume. After cooling, the precipitated crystals are filtered off with suction, washed with 35 ml of acetone and dried at 60 ° C. to constant weight. You get. H $ , 5 g of the sodium salt of 2,6-dioxocyclohexanethiocarboxylic acid-Jj'-chloranilide of the composition

Example 2

Potassium salt of 2, o-Dioxocyclohexanthiocarbonsäure- h '-chloranilids

6/6 g of potassium hydroxide (85 %) are dissolved in 200 ml of water and 28 g of 2,6-dioxocyclohexanthiocarboxylic acid 4'-chloranilide are added to this solution with stirring. The mixture is stirred for 15 minutes, the solution is filtered and evaporated to a small volume in vacuo at 50.degree. After cooling, the precipitated crystals are filtered off with suction, washed with 30 ml acetone and dried at room temperature to give 25 g potassium salt of 2,6-Dioxocyclohexanthiocarbonsäure h '-chloranilids of the composition C ₁ H ^ ₁

Example 3

Calcium salt of 2, ö-Dioxocyclohexanthiocarbonsäure- ¹ ! '-chloranilids

2.8 g of pure calcium oxide are stirred in 200 ml of water for 1 hour, 28 g of 2,6-dioxocyclohexanthiocarboxylic acid- ^ ¹ -chloranilide are added and the mixture is stirred for a further 1 hour. The solution is filtered and evaporated to a small volume in vacuo at 50 ° C. After cooling, the precipitated crystals are filtered off with suction with 40 ml of acetone

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washed and ^kneaded _{over P 2} ⁰ S 6 etroc. 15 g of calcium salt of 2, o-dioxocyclohexanthiocarboxylic acid-iJ'-chloranilide of the composition (C.-H

Example ^

Lithium salt of 2, o-Dioxocyclohexanthiocarbonsäure- *! '-chloranilids

In a solution of 2, U g of pure lithium hydroxide in ¹ 100 ml of water, 28 g of 2, δ-dioxocyclohexanthiocarboxylic acid- ¹ ! '-chloranilide registered. Further processing is carried out according to the procedure of Example 1. 15> 8 g of lithium salt of 2, o-dioxocyclohexanthiocarboxylic acid ¹ ! ' -chloranilids of the composition CL, H .ClLiNOpS.

Example 5

Sodium salt of 2,6-dioxocyclohexanethiocarboxylic acid 't'-chloroanilide

2.3 g of sodium are reacted in 800 ml of anhydrous ethanol. To the sodium ethylate solution are added 28 g of 2, δ-dioxocyclohexanthiocarboxylic acid- ¹ ! '- chloranilide and heated under reflux for 15 minutes. The hot solution is filtered, cooled, the crystals are filtered off with suction, washed with 10 ml of ethanol and dried to constant weight. 22 g of the sodium salt of 2,6-dioxocyclohexanthiocarboxylic acid-4'-chloranilide of the composition Ο ^, Η are obtained

Example 6

Sodium salt of 2,6-Dioxocyclohexanthiocarbonsäure- ⁱ <'-bromanilids

33 g of 2, o-dioxocyclohexanthiocarboxylic acid-M′-bromanilide are introduced into a solution of 4.1 g of sodium hydroxide (98 %) in 300 ml of water, with stirring. It is stirred for 30 minutes, the solution is filtered and evaporated in vacuo at 5O ⁰ C until the onset of crystal precipitation a. After adding 60 ml of acetone, the mixture is cooled, the crystals which have separated out are filtered off with suction and washed with 30 ml of acetone

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and dries at 70 ° C to constant weight. 23 g of the sodium salt of 2,6-dioxocyclohexanethiocarboxylic acid ⁱ l'-bromanilide of the composition C., H .BrNNaO S.

Example 7

Manufacture of a tap water-soluble dry preparation

2,6-Dioxocyelohexanthioearboxylic acid

4'-chloroanilide potassium salt 10,000 g

Polyglycol 4000 0.500 g

Potassium carbonate 0.515 g

Tetrasodium edetate. 1.485 g

12,500 g

The substances are mixed together. To improve the flowability, the mixture is compacted on a roller and the scabs obtained passed through a granulator (mesh size 1.5 mm).

The granules obtained dissolve 1 JSig in tap water within 2 minutes. ¹

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Claims (10)

- 9 -. hoe 73 / F 097 claims .'Alkali and alkaline earth salts of compounds of the formula -NH-f Vi wherein X represents a halogen atom. 2. Lithium salt of 2,6-Dioxocyclohexanthiocarbonsäure- ¹ I '- ch lor ani Ii ds 3. Sodium salt of 2,6-dioxocyclohexanethiocarboxylic acid M'-chloranilide ¹ I. Potassium salt of 2, o-Dioxocyclohexanthiocarbonsäure- 4 · - ch lor ani Ii ds 5. Calcium salt of 2,6-Dioxocyclohexanthiocarbonsäure- Ί'-chloranilide 6. Sodium salt of 2,6-dioxocyclohexanethiocarboxylic acid M'-bromanilids 7. Fungal skin preparations containing at least one compound according to claim 1 and optionally a complexing agent and / or other auxiliary materials. 8. Fungal skin preparation containing at least one compound according to Claims 2 to 5 and optionally a complexing agent and / or other auxiliary materials. 9. A process for the preparation of compounds according to claim 1, characterized in that 2, o-dioxocyclohexanthiocarboxylic acid ip-haloanilides with an alkali or alkaline earth oxide, bicarbonate or alcoholate. 10. Use of compounds according to claim 1 as an antifungal agent. 409843/1088