DE3016110C2 - - Google Patents

Description

The invention relates to chlorhexidine salts, process to their preparation and containing these compounds Medium.  

Chlorhexidine, nalidixic acid, phosphanilic acid and sorbin Acid are known in the art. About that In addition, from US-PS 39 60 745 and 38 55 140 also certain chlorhexidine salts known. These include that Hydrochloride, gluconate, isethionate, formate, acetate, Glutamate, succinamate, monodiglycolate, dimethanesulfonate, Lactate, di-isobutyrate and glucoheptonate.

Polyhydroxycarboxylic acid salts of diguanides, such as Chlorhexidine di-D-gluconate, are in the US-PS 29 90 425 described as slightly soluble in water.

The oral antibacterial use of water-soluble Chlorhexidine salts, such as the gluconate, acetate, fluoride, Dihydrogen fluoride and dihydrogen chloride, is in the US-PS 39 76 765 described.

An oral antibacterial agent consisting of a Combination of dodecyl-di- (aminoethyl) -glycine and Chlorhexidine or its digluconate, diacetate, dichloride or monofluorophosphate salts is disclosed in US-PS 39 32 607th described.

Chlorhexidine salts with certain sequestering amino Carboxylic acids are described in US Pat. No. 3,888,947. preferred Salts are mono-chlorhexidine nitrilotriacetate, tri-chloro hexidine di (diethylene triamine pentaacetate), mono chlorhexidine di (N, N-dihydroxyethylaminoacetate), mono-chlorhexidine-N- hydroxyethylenediamine triacetate and mono-chlorhexidine di- (N-hydroxyethyl-ethylenediamine triacetate). It is stated that such sequestering agents have a stronger antibacterial Have the effect as the corresponding diguanide salt (see. Column 3, lines 22 to 42 of the patent specification).

Bis-guanid-hydroxyalkane sulfonic acid salts are in the British Patent 815,800. It will be  claims that such salts (including the Isäthion acid salt, of the 2: 3-dihydroxypropane-1-sulphonic acid salt, of the 3-chloro-2-hydroxypropane-1-sulfonic acid salt and the 2-hydroxypropane-1-sulfonic acid salt) in water very well are soluble.

US-PS 31 52 181 describes monodiguanides with at least an alkoxypropyl group having 11 to 19 carbon atoms at the N¹ or N⁵ nitrogen atoms. It is claimed, that these compounds are excellent antimicrobial Have properties and in the form of the free base, or if Water solubility is important for use in Form of salts with inorganic and organic acids (such as mono- and polycarboxylic acids and sulfur-containing Mono- and polyacids and acidic nitrogen compounds) can be used. Examples of such salts are the Hydrochloride, hydrobromide, sulfate, phosphate, borate, Phosphite, sulfite, sulfonate, nitrite, carbonate, nitrate, Acetate, tartrate, propionate, oxalate, maleate, malate, Picrate and β-ethoxypropionate salts. Examples of suitable acidic nitrogen compounds are theophylline, substituted Theophylline and similar purines, saccharin, phthalimide, Benzoxazine-2,4-diones, oxazolidine-2,4-diones and substituted ones oxazolidone-2,4-diones, N-p-methylbenzene-sulfonyl-N'-n-butyl urea, barbituric acids, mercaptobenzothiazole, 8-chloroheo phylline and succinimide. In the patent is (in Column 11, lines 36 to 70) indicated that this mono Diguanide can be used together with other medicines can.

As stated above, nalidixic acid, phosphanil acid and chlorhexidinic acid according to the prior art known. The antibacterial agent nalidixic acid (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3- carboxylic acid) is the subject of US Pat. No. 3,590,036.  

It is not known that nalidixic acid has been topically was turned.

Phosphanilic acid (p-NH₂C₆H₄PO₃H₂, 4-aminobenzene phosphonic acid) was synthesized (by i.a Doak et al JACS 74 (1952)) and found to be active against various organisms (cf. Kuhn et al., Ber. 75, 711 (1942); Klotz et al., JACS 69,473 (1947); and Thayer et al., Antibiotics and Chemotherapy, 3,256 (1953)).

US Pat. No. 3,159,537 teaches that certain phosphonic acid compounds, including phosphanilic acid, the oral absorption of Increase tetracycline antibiotics (i.e., increase blood levels).

Complexes of phosphanilic acid and an aminoacridine compound (preferably 9-amino, 3-amino or 6-amino-acridine) in the US-PS 36 94 447 and 37 94 723 as antibacterial and described antifungal.

It has also been reported that phosphanilic acid with trimethoprim against a variety of bacteria synergistic effect have shown (US-PS 41 25 610). It is also from a synergistic effect with neomycin and streptomycin against Enterobacteriaceae reports (Ciencia (Mexico) 17, 71-73 (1975)).

Finally, it should be noted that the topical, infection inhibiting chlorhexidine (1,6-di (N-p-chlorophenyldiguanido) hexane has long been known, US-PS 26 84 924.

The present invention is based on the object new Chlorhexidine salts with superior antibacterial To provide effect.  

This problem has been solved by making compounds the general formula:

provided in which
X is selected from sorbic acid, nalidixic acid and phosphanilic acid.

chlorine hexidine disorbate is preferably used in the form of Monohydrate, while chlorhexidine diphosphanilate as Dihydrate applies.  

These new antibacterial compounds can be applied to one manner can be prepared by, for example the desired acid, dissolved in a suitable one Solvent, preferably hot ethanol with nalidixine acid and sorbic acid and hot water in phosphanil acid, with chlorhexidine in the form of the free base, dissolved in a suitable solvent, preferably hot Ethanol or hot methanol, converts.

The resulting precipitate is collected, washed and then recrystallized by conventional methods, then obtaining the novel salt according to the invention.

The following examples are intended to illustrate the preparation of illustrate new salts according to the invention in more detail.

Example 1

A solution of 505 mg (1.0 mmol) chlorhexidine in the form of free base in 50 ml of hot ethanol is added carefully a hot solution of 464 mg (2.0 mmol) nalidixic acid in 50 ml of hot ethanol. It immediately results in a low which is filtered off after the mixture has cooled is. The collected precipitate is consecutively with Ethanol, chloroform and then washed with ether. Than it will be the washed solid precipitate of dimethylformamide (DMF) recrystallized, with 0.6 g (corresponding to an Off prey of 61.9% of theory) of a whitish, solid Chlorhexidine dinalidixinats receives.

Mp 224-226 ° C.
IR (KBr): bands at 3330-2860 (broad multiplet), 1625, 1492, 1445, 1252, 1132, 1092, 820 and 745 cm ^-1 .

Analysis C₄₆H₅₄Cl₂N₁₄O₆:
calculated:
C 56.96 H 5.61 N 20.21 Cl 7.31 O 9.90%
found:
C 56.86 H 5.74 N 20.21 Cl 7.25%

example 2

A warm solution of 505 mg (1.0 mmol) of chlorhexidine in the form the free base in 50 ml of methanol is added to a solution of 346 mg (1.0 mmol) of phosphanilic acid in 250 ml of hot Water. The resulting solution is then about 50 ml concentrated and cooled, leaving a waxy solid separates. The waxy solid is filtered off, with Washed water and then recrystallized from water.  

After drying, 205 mg of chlorhexidine diphosphanilate are obtained dihydrate. FP 172-174 ° C. This means a yield of 23.1% of theory.

(Am = 51,600)
IR (KBr): bands at 3460 to 2930 (broad multiplet), 1650 to 1600 (broad multiplet), 1515, 1490, 1420, 1130 and 828 cm ^-1 .

Analysis C₃₄H₅₀Cl₂N₁₂O₈P₂:
calculated:
C 45.99 H 5.67 Cl 7.98 N 18.93 O 14.42 P 6.97%
found:
C 45,94 H 5,75 Cl 8,25 N 19,00 P 6,85%

example 3

A hot solution of 224 mg (2.0 mmol) of sorbic acid in 10 ml Ethanol is added to a hot solution of 505 mg (1.0 mmol) Chlorhexidine in the form of the free base in 50 ml of ethanol. The The resulting solution is concentrated to a solid. Than it will be the solid from ethanol / isopropanol (1: 1 parts by volume) crystallized. The crystalline product thus obtained becomes dried, taking 527 mg of chlorhexidine disorbate monohydrate receives. The chlorhexidine disorbate monohydrate falls as white Powder, which shrinks at 90 to 100 ° C and at 100 to 104 ° C melts. The recovered chlorhexidine disorbate monohydrate amount corresponds to a yield of 70.5% of Theory.  

IR (KBr): bands at 3460 to 2870 (broad multiplet), 1650 to 1600 (broad multiplet), 1540, 1490, 1390, 1000 and 825 cm ^-1 .

Analysis C₃₄H₄₈Cl₂N₁₀O₅:
calculated:
C 54.61 H 6.47 Cl 9.49 N 18.73 O 10.70%
found:
C 54.87 H 6.65 Cl 9.68 N 18.49%

The compounds prepared according to Examples 1 and 2, chlorhexidine dinalidixinate and chlorhexidine diphosphanilate are tested in vitro for their activity against 32 strains Pseudomonas aeruginosa, 26 strains of other gram-negative organisms and 18 gram-positive organisms. The MIC values for the reference compounds, chlorhexidine digluconate, chlorhexidine diacetate, nalidixic acid and phosphanilic acid are also determined. Chlorhexidine in the form of the base could not be used as a reference since it is unstable. The experimental results are summarized in Table I below:

The values of Table I show that the chlorhexidine-dinali dixic acid salt is more effective against many of the strains studied is as nalidixic acid or chlorhexidine alone. From the Values show that chlorhexidine-dinalidixinat especially is effective against all P. aeruginosa strains as well as against individual K. pneumonia, E. cloacea and P. morganii strains, while chlorhexidine diphosphanilate countered 26 of 32 P. aeruginosa strains and against a P. mirabilis and a P. vulgaris strain is particularly effective.

The results in Table I show that the chlorhexidine nalidixic acid salt is more effective than either Components that make up it.

To the synergistic effect of the new invention Salts, chlorhexidine dinalidixinate, Chlorhexidine disorbate and chlorhexidine diphosphanilate, and nalidixic acid, phosphanilic acid, Chlorhexidine diacetate and a 1: 1 mixture of chlorhexidine digluconate and nalidixic acid on their in vitro activity against 30 strains Pseudomonas aeruginosa, 23 strains of others gram-negative organisms and 15 gram-positive organisms tested. It was the MIC concentrations for the new, he salts according to the invention and for the comparative compounds (näm chlorhexidine digluconate, chlorhexidine diacetate, chlorine hexidine disorbate, nalidixic acid, phosphanilic acid and the 1: 1 mixture of chlorhexidine digluconate and nalidixic acid) determined. In contrast to that used in Table I. Procedures were all compounds on a weight basis and in a medium containing a low level of antibiotic Antagonist has (Mueller-Hinton broth + 1% Ionagar) tested, so the antiobiotic sensitivity to increase.  

The results summarized in Table II below demonstrate that chlorhexidine dinalidixinate is more effective than either chlorhexidine or nalidixic acid alone, especially against strains of Klebsiella pneumoniae and Enterobacter cloacae, and 28 out of 30 strains of P. aeruginosa. The Chlorhexidin- phosphanilsäuresalz shows a clear improvement against phosphanilic acid and chlorhexidine alone in 4 of 30 strains P. aeruginosa. The results also show that chlorhexidine diphosphanilate is a very effective antipseudomonas agent. It inhibits 29 of the 30 P. aeruginosa strains at MIC values of 8 γ / ml or less compared to chlorhexidine digluconate, diacetate and disorbate, which show inhibitory activity against only 2 strains at a concentration below 8 γ / ml.

To the unexpected synergistic effect of the new, he make the salts according to the invention even clearer, were the MIC values shown in Tables I and II in γ / ml, in μmol / ml using the repositioned molecular formulas and molecular weights converts:

Chlorhexidine disorbat monohydrate C₃₄H₄₈Cl₂N₁₀O₅ 747.72 Chlorhexidine dinalidixinat C₄₆H₅₄Cl₂N₁₄O₆ 969.94 Chlorhexidine diphosphanilat dihydrate C₃₄H₅₀Cl₂N₁₂O₈P₂ 856.72 Chlorhexidine digluconate C₃₄H₅₄Cl₂O₁₄N₁₀ 897.80 Chlorhexidine diacetate C₂₆H₃₈Cl₂N₁₀O₄ 625.56 nalidixic C₁₂H₁₂N₂O₃ 232.23 Phosphanilsäure C₆H₈NO₃ 142.13

Tables III and IV show the results of this conversion and allow a comparison on a molecular basis which is more informative than the comparison on a weight basis.

The results of Table III show that the new ones, he chlorhexidine dinalidixinate and diphosphanil according to the invention acid salts are effective and act synergistically, in particular against P. aeruginosa, where the nalidixinate salt is the largest shows synergistic effect. The new invention Disorbate salts show a clear opposite to some species synergistic effect. The synergistic effect of chlorine hexidine-dinalidixinate is clearly indicated by an Ver equal to the values of Table III for K-pneumonia, E. cloacae, P. mirabilis, P. morganii, P. rettgeri, P. vulgaris, S. marces cens, P. stuartii and P. aeruginosa. For example Chlorhexidine dinalidixinate has an MIC value of 2.9 against 2 Strains K-pneumoniae and 8.2 against a strain of this organism. The corresponding values for nalidixic acid are 48.7 and 68.9; the values for chlorhexidine digluconate and chlorhexidine diacetate are respectively 70.1 and 35.6 and 51.1 and 51.1.

The novel chlorhexidine dinalidixinate according to the invention shows the most impressive synergistic action against P. aeruginosa. Against 26 strains of this organism has chlorhexidine-dinalidixinat an MIC of 50.1; against 5 strains of these organisms the MIC value is 43.2, while it is against a trunk of such Organism has a MIC of 32.9. In contrast, has Nalidixic acid against these strains MIC levels, which in each Fall above 539, with chlorhexidine digluconate and Chlorhexidine diacetate against the same strains MIC values of in each case more than 139, more than 139 and 139 and more than 200, 200 and 200 showed.

The synergistic effect of chlorhexidine dinalidixinate also clearly results from the results of Table IV. Synergism is discernible against K. pneumoniae, E. cloacae, P. mirabilis, P. rettgeri, S. marcescens, P. stuartii and P. aeruginosa.  

Likewise from Table III shows that the fiction chlorhexidine diphosphanilate a pronounced synergistic action against S. viridans, P. mirabilis, P. vulgaris, a strain of P. stuartii and numerous Strains P has aeruginosa.

Table IV demonstrates the assumed synergism of chlorhexidine diphosphanilate against a P. rettgeri strain and numerous P. aeruginosa strains.

Table IV further shows that the synergistic Effect of chlorhexidine disorbate is most pronounced against S. pyogenes, a P. rettgeri strain and numerous P. aeruginosa strains.

The invention also relates to a process for the preparation of compounds of the general formula:

wherein
X is selected from sorbic acid, nalidixic acid and phosphanilinic acid,
wherein the sorbic acid, nalidixic acid or phosphanilic acid in a suitable solvent dissolves, preferably, hot ethanol at nalidixic acid and sorbic acid and hot water at phosphanilic acid, and therein with chlorhexidine in the form of the free base, dissolved in a suitable solvent, preferably hot ethanol or hot methanol, reacted and, if appropriate, the resulting precipitate, washed, and then recrystallized.

The invention also relates to antibacterial dermatological Agents which at least one inventive chlorhexidine salt and a dermatologically acceptable carrier.

Suitable agents are creams, lotions, suspensions, Emulsions, ointments and pastes.

Also within the scope of the present invention are means, in which a novel, according to the invention Chlorhexidinsalz in is prepared as by reaction of chlorhexidine and sorbic acid; by reaction of chlorhexidine and Nali dixinsäure; or by reaction of chlorhexidine and Phosphanilsäure.

The compounds of the invention are in a proportion of 0.1-10 wt .-% in the antibacterial agents, preferred in an amount of 0.25 to 5% by weight, and most preferably zugt in a proportion of 0.75 to 2.5 wt .-% contained.

The formulations described below are intended to be the illustrate means of the invention.  

The formulations listed in Table V below 1-6 are prepared by the following general procedure.

In a container of suitable size, the stearyl alcohol is dissolved in petrolatum, heating and stirring gently. Then the temperature is set to 62 to 68 ° C.

Propylene glycol and about 99% of the purified water in a, preferably provided with a heating jacket main Combined mixing vessel of suitable size and stirred until man receives a homogeneous solution. The resulting solution is heated one then at 62 to 68 ° C and then mixes with great speed (preferably using a suitable propeller mixers, such as Lightnin model ARL air mixer or one similar device). To do this, slowly add the carbomer. Continue mixing at high speed until the carbomer is completely dispersed (about 1 hour). Subsequently Sodium lauryl sulfate, sorbic acid, and Amphoteric-9 are added to, mixing slowly and the resulting mixture on mix slowly until homogeneous.

In a suitably large container to heat the rest Water (about 1%) to about 40 to 45 ° C and then gives rapidly stir the dried sodium phosphate and stir continue until you get a clear solution. Then you give the clear sodium phosphate solution to the mixture in the main mix mixing slowly and continue mixing, until you get a smooth semi-gel. During the slow Mixing one begins to mention and sets the temperature then at about 62 to 68 ° C.

Petrolatum and stearyl alcohol, which are the oil phase, Then you slowly into the main mixing vessel, which is the Contains components of the aqueous phase. During this Addition, the aqueous phase is mixed at high speed. After another 5 to 10 minutes of mixing you start with the  Cooling (preferably by introducing cold water into the outer shell of the main mixing vessel. You mix with it low speed (preferably using a the side walls stripping trouser leader of the type Groen. The mixture is cooled to about 25 to 30 ° C. where you get a ready basis.

A small amount of the finished base (sufficient to make a Processing required consistency: about 5% at Formulations 1 and 4; about 10% in the formulations 2 and 5 and about 15% in the formulations 3 and 6) are in a suitably large container. One adds the invention Chlorhexidinsalz new and mixed it (with the help of a Spatula or a suitable mixer) until finished Lotion base is uniformly dispersed. You give the dis persion through a roller mill (preferably of the type Asra) with a suitable setting, so that you have a fine does not get gritty mass. If necessary again one gets these procedures, whereby a ground concentrate receives.

The ground concentrate is then added to the remaining finished Basis, it mixes with it at low speed (preferably using a brush stirrer) while one hour or until a uniform dispersion has formed.  

Table V

The formulations listed in Table VI below 7, 8 and 9 are according to the following general procedure manufactured:

Peg-8 and lactic acid are added in a suitably large size Mixer, preferably made of stainless steel, and mixed slowly until to get a homogeneous solution.

Petrolatum, mineral oil, lanolin oil, cetyl alcohol, hydrogenated Polyisobutene, Peg-40 Stearate, Benzyl Alcohol and Sodium Lauryl Sulfate is added to a main mixing vessel, preferably from Consists of stainless steel and has a steel jacket (eg. Large model TDC / 2-20). Stir the mixture slowly (preferably with a Lightnin air mixer, equipped with propeller blades) and heated. Stir and heat until all solids melted, the temperature sets to about 65 to 70 ° C. on, mix for about 10 minutes and then listen to the Heat and stir. The mixture is cooled (preferably by introducing cold water into the outer jacket) and mixes at low speed (preferably with a sweeper stirrer scraping off the side walls). Then allowed to cool the mixture to about 40 to 45 ° C, without to stop mixing.

The solution of lactic acid and Peg-8 are then slowly added to the Oil phase-forming constituents in the main mixer, wherein one constantly stirring. Mix and then cool further a temperature of 25 to 30 ° C and thus receives a finished Basis.

A small amount of the finished basis (enough to make a ver maintain workable consistency; about 5% in formulation 7, about 10% for formulation 8 and about 15% for formulation 9) Are you in a suitable large mixing vessel (for example  Horbart Model A-200 D) releases the chlorine hexidine diphosphanilate and stir the combination of Chlorhexidine diphosphanilate and finished base slowly until to obtain a fairly uniform dispersion of the salt. The dispersion is passed through a roller mill (preferably Asra type) and adjusts accordingly so that a fine, non-gritty mass than ground Concentrate receives.

The ground concentrate is then added to the finished and mixed at low speed (preferably using a sweeper-stirrer, which sides off scrap, type Groen about 1 hour or until you get receives a homogeneous dispersion.  

Table VI

The formulations listed in Table VII below 10, 11 and 12 are according to the following general procedure Wise made:

Glyceryl oleate / propylene glycol, Peg-7 hydrogenated castor oil, Sorbitan oleate, oleoyl-hydrogenated animal protein, Arlacel 481, light mineral oil, hydrogenated polyisobutene, Lanolin alcohol / mineral oil, caprylic / capric triglycerides, Propyl paraben and beeswax are sufficient in one large pre-mixer, which is preferably made of stainless steel and an outer jacket has given. The mixture is heated with slow mixing (preferably with a Lightnin Model ARL air mixer with propeller or similar stirring device), the temperature is at about 75 to 85 ° C. and receives thereby an oil phase.

Water, lactic acid, propylene glycol and dried sodium Phosphate is also added to a mixer, preferably made of stainless steel and provided with an outer sheath (eg Groen Model TDC / 2-20). During the addition mixes and heated at a moderate speed (preferably using a Lightnin model ARL mixer). Mix until you get a clear solution then add sorbitol, methyl paraben and titanium dioxide, mix and continue heating until a homogeneous mixture is obtained lies. Set the temperature to about 75 to 85 ° C, whereby an aqueous phase is obtained.

When the water and oil phases are at the right temperature are enough, you give the oil phase slowly under constant Mix at moderate speed to the water phase (preferably using a Lightnin Model ARL Air mixer), whereby one receives an emulsion. Then you give the magnesium stearate to the emulsion and mix it in for about 20 minutes a temperature of about 75 to 85 ° C with it.  

Then you stop warming up (preferably by initiating of cold water into the outer shell of the main mixing vessel, starts to mix slowly (preferably using a brush stirrer, such as Groen Model TDC / 2-20), mixes and cools until the temperature has reached about 25 to 30 ° C and you have a finished base is present.

A small amount of the finished base (sufficient to make a processable consistency, about 5% in Formu 10, about 10% for formulation 11 and about 15% for Formulation 12) is in a sufficiently large Container. The novel chlorhexidine according to the invention is added salt and mix with a spatula or similar Mixer until a fairly uniform dispersion of the Getting salt in the ointment base. This dispersion gives one or more times by a roller mill suitable Capacity (preferably type Asra) at ent speaking attitude, so that you are a fine, not Grießige mass as a ground concentrate receives.

The ground concentrate is then added to the rest Base and mix it slowly for about 1 hour with it (preferably using a Groen Feger stirrer) until a homogeneous dispersion is obtained.

The term used in formulation 10 is Arlacel 481 is a trade name and represents one Mixture of sorbitan oleate, hydrogenated castor oil, bees wax and stearic acid.  

Table VII

Mixtures of chlorhexidine or pharmaceutically acceptable Chlorhexidine salts (eg chlorhexidine digluconate) with Nalidixic acid or pharmaceutically acceptable nalidixic acid Salts show synergistic effects when used, to the growth of microorganisms, such as Klebsielle pneumoniae, to prevent enterobacter cloacae and pseudomonas aeruginosa. The calculated synergism index numbers show that this Mixtures 35 to 65 wt .-% chlorhexidine or a pharma ceutically compatible chlorhexidine salt and 65 to 35% by weight Nalidixic acid or a pharmaceutically acceptable nalidixine should contain acid salt. Preferably, these should Blends about equal parts by weight of each of the two above mentioned pharmaceutically acceptable compounds.

Mixtures of chlorhexidine or pharmaceutically acceptable Chlorhexidine salts (eg chlorhexidine digluconate) with Phosphanilic acid or a pharmaceutically acceptable Phosphanilic acid salt also show synergism when to inhibit the growth of microorganisms, such as Staphylococcus aureus, streptococcus pyogenes, streptococcus faecalis and pseudomonas aeruginosa. These mixtures may be about 35 to 65 wt .-% chlorhexidine or a pharma ceutically acceptable chlorhexidine salt and about 65 to 35 wt .-% of phosphanilic acid or a pharmaceutically acceptable containing Phosphanilsäuresalzes. Preferably included these blends about equal proportions in weight percent of the above listed pharmaceutically acceptable compounds.

Claims (3)

1. Compounds of the general formula: wherein:
X is selected from sorbic acid, nalidixic acid and phosphanilic acid. 2. A process for the preparation of the compounds according to An Claim 1, characterized in that one Sorbic acid, nalidixic acid or phosphanilic acid in one suitable solvent, preferably in hot Ethanol with nalidixic acid and sorbic acid and hot Water in phosphanilic acid, dissolves and in it with chlorine hexidine in the form of the free base, dissolved in a suitable Solvent, preferably hot ethanol or hot Methanol, reacting and optionally the resulting lower washes and then recrystallized. 3. Antibacterial agent containing at least one Ver Binding according to claim 1 in a dermato logically compatible carrier.