DE2223766A1 - Bis-biguanide salts, processes for their preparation and their use - Google Patents

Description

Bis-biguanide salts, processes for their preparation and their use

The invention relates to bis-biguanide salts, processes for their preparation and their use, in particular as. Bactericides in human or veterinary medicine.

It is known that bis-biguanides generally determined have bactericidal properties. In particular, a compound, ljö-bis-CN.-p-chlorophenyl-diguanido-NcJ-hexane, with the international generic name, "Chlorhexidine", has been used in medicine found widespread use as a bactericidal agent, generally as a disinfectant. However the bis-biguanide bases known to date and most of their salts show only very low solubility in water, so that their use as a disinfectant, which is well known

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mostly present in aqueous solution, which is limited.

The invention relates to new bis-biguanide salts with excellent Solubility in water, which therefore allows a much cheaper application than disinfectants and bactericides.

Surprisingly, it was found that salts are better known bactericidal bis-biguanidbasen with amino-carboxylic acids acting as sequestering agents a much stronger bactericidal Have activity than previously known salts of biguanide bases.

In particular, compounds of the general Formula I.

A-NH-C-NH-C-NH-X-NH-C-NH-C-NH - ~ A

η ι ι ι

NH NH NH NH

are used, in which A identical substituted or unsubstituted phenyl or alkylphenyl groups, where the alkyl group can have 1 to 3 carbon atoms, and in which one or more halogen atoms or hydroxyl, nitro, alkyl, alkoxy as a substituent of the phenyl groups - Or alkylthio groups may have occurred and in which X has a bridging function through a benzene, dialkoxybenzene or cyclohexane ring, through diphenylmethylene or polymethylene chains with 1 to 15 -CH ₂ - groups, which optionally

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be interrupted by one or more oxygen atoms can and / or optionally can be interrupted or terminated by one or more benzene rings, or in which X is the group -NH-X-NH- (that is, X together with two Imino groups) which are closed to form a piperazinyl ring.

Preferred bis-biguanide bases used for the preparation of the salts are:

1,2-bis (N ₁ -p-chlorophenyldiguanido-N ₅ ) ethane;

top-bis- (N ^ -p-chloropheny ldiguanido-N, -) - di-n-propyl ether;

1,6-bis- (Nj-ß-phenylethyldiguanido-N, -) -hexane; 1,6-bis - (N ^ -pheny ldiguanido-N, -) -hexane; 1,6-bis (N ₁ ^, M-dimethylphenyl diguanido-N, -) hexane; 1,6-bis (N 1 - p -tolyldiguanido-N -) - hexane; '1,6-bis- (N ₁ -p-hydroxyphenyldiguanido-Nj -) - hexane;' 1,6-bis- (N ^^ - p-anisy idiguanido-N, -) - hexane; 1,6-bis- (N 1- m -nitrophenyl diguanido-N, -) hexane; 1,3-bis (N ₁ -p-chlorophenyldiguanido-Nc) propane; 1,4-bis (N ₁ -p-chlorophenyl diguanido-Nc-) butane; 1,5-bis (N ₁ -p-chlorophenyldiguanido-N ₅ ) pentane; 1,7-bis- (N.-p -chlorophenyldiguanido-Nc) -heptane; 1,6-bis- (N ^ -m-chlorpheny ldiguanido-N p.) - hexane; 1,6-bis (N ^ -2,5-dichlorophenyldiguanido-Nc) hexane;

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1,6-bis - (N ₁ - 3, ¹ I-di.chlorpheny Idiguanido-Nc) hexane; 1,4-bis- (ϊ ^ -phenyldiguanido-Nj-) -benzene; !, ^ - Bis-CN ^ -p-chlorophenyldiguanido'-Nf -) - benzene j 1,6-bis- (N ^ -p-chlorophenyldiguanido-Nj-) -hexane; l, 10-bis (N ₁ -p-chlorophenyldiguanido-N, -) - decane; 1,4-bis (Nj-o-chlorophenyldiguanido-Nc) hexane; ¹ J, 4 '-Bis- (N 1 -phenyldiguanido-Nj-) -diphenylmethane; 4, I * '-Bis- (N ₁ -p-chlorophenyldiguanido-N _t -) -diphenylmethane; Co / LD'-Bis-CN ^ -p-chlorophenyldiguanido-NcJ-l ^ -di-n-propoxybenzolj 1,4-bis- (N.-p -chlorophenylamidinoamino-N ^) -piperazine; (according to another nomenclature bis- (N ₁ -p-chlorophenyldiguanido-Nc> Ncbis-ethylene).

The following are preferably used:

1,6-bis- (N.-p-chlorophenyldiguanido-NfJ-hexane (generic name "Chlorhexidine") and

1,4-bis- (N ^ -p-chlorophenylamidinoamino-Nij) -piperazine (generic name "Picloxidine").

Of the amino carboxylic acids known as sequestering agents, in particular compounds are used for salt formation which _{correspond to the general formula HOOC CH 2} N (R ¹ ) ZR ² (II), where R is a hydrogen atom, an alkyl, carboxy

methyl, hydroxyethyl or hydroxypropyl group, R a

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Carboxymethyl, hydroxyethyl or hydroxypropyl group and Z either the group - "CH ₃ .CH ₃ .N (R ³ ) _n ~, where R ³ in the definition corresponds to R and η can be 0, 1, 2 or 3, or in the Z the group

(III) in which R has the meaning already given.

Corresponding amino-carboxylic acids of the general formula II are for example:

1 2 "" 5 Ethylenediamine tetraacetic acid (EDTA) - η = 1 and R, R and R- ^

mean carboxymethyl;

Ν, Ν'-ethylenediamine diacetic acid (EDDA) - η = 1, R ¹ and R ⁵ be—

ρ denote hydrogen atoms and R denotes carboxymethyl;

N-hydroxyethyl> -ethylenediamine-triacetic acid (HEDTA) - η = 1,

R and R are carboxymethyl and R ^ is 2-hydroxyethyl;

NjN'-Dihydroxy-ethylenediamine-diacetic acid (HEDDA) - η - 1, · R ¹

2 ^

and R is 2-hydroxyethyl and R ^J is carboxymethyl;

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Diethylenetriamine-pentaacetic acid (DTPA) - η = 2 and R, R ² and both R are carboxymethyl;

1,2-Diaminocyclohexane-tetraacetic acid (CDTA) - R, R and R
mean carboxymethyl;

1 nitrilotriacetic acid (NTA) - η = 0 and R and R are carboxymethyl;

N-hydroxyethyl-iminodiacetic acid (HIMDA) - η = 0, R ¹ = 2-hydroxy

ethyl and R is carboxymethyl;

1 2 Ν, Ν-dihydroxyethyl-aminoacetic acid (DAA) - η = 0 and R and R

mean 2-hydroxyethyl;

Iminodiacetic acid (IMDA) - η = 0, R means hydrogen and

R is carboxymethyl;

3-hydroxypropyl-iminodiacetic acid (HPIMDA) - η = 0, R = 3-hydr'oxy-

propyl and R means carboxymethyl.

Mostly EDTA, HEDTA ₁ DTPA, NTA or DAA and preferably HEDTA and DAA are used.

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The salts according to the invention arise as a reaction product from the reaction of the acid groups of the aminocarboxylic acids and the basic functions of the bis-biguanide and can therefore not only be regarded as salts but also as sequestering agents will. The salts can be the starting compounds, so Acid and base, contained in varying amounts, since the mostly polybasic acids and the mostly polyacid bases are in can implement various stoichiometric ratios »In general, the basic bis-biguanides react as two-acidic ones Bases, that means that there is one basic puncture in each case reacts in the symmetrical halves of the molecule, while the aminocarboxylic acids are preferably monobasic or dibasic Acids, which means that either "one or two acid groups puncture, react. - -" ■

This is how the preferred bis-biguanide reacts, for example Chlorhexidine as a two-acid base, while the preferred aminocarboxylic acid HEDTA is either mono- or dibasic Reaction reacts so that predominantly only chlorhexidine mono-HEDTA-at, where HEDTA reacts as a dibasic acid., and Form chlorhexidine-di-HEDTA-ate, with HEDTA acting as a monobasic acid in the latter case.

By converting the various bis-biguanides and aminocarboxylic acids numerous salts can be produced. The following salts, for example, are preferred:

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Mono-chlorhexidine-ethylenediamine-tetraacetate (abbr .: Chlorhex /

EDTA);

Monochlorhexidine nitrilotriacetate (abbr .: Chlorhex / NTA); Tri-chlorhexidine-di-l diethylenetriamine-pentaacetatlf

3 chlorhex / 2 DTPA);

Mono-chlorhexidine-di-j Ν, Ν-dihydroxyethyl-aminoacetate J (abbr .:

Chlorhex / 2 DAA);

Mono-picloxidin-ethylenediamine-tetraacetate (abbr .: Pic / EDTA);

Mono-picloxidin-nitrilotriacetate (abbr .: Pic / NTA); Mono-picloxidin-di- [Ν, Ν-dihydroxyethyl-aminoacetate] (abbr .:

Pic / 2 DAA);

Mono-picloxidin-diethylenetriamine-pentaacetate (abbr .: Pic / DTPA);

Mono- IJ., 6-bis- (N ^ -p-methylthiophenyldiguanido-Nc) -hexaneJ-N-

hydroxyethyl ethylenediamine triacetate (abbr .: Methiohex / HEDTA);

Mono-chlorhexidine-N-hydroxyethyl-ethylene-diamine-triacetate (Abbr .: Chlorhex / HEDTA);

Mono-chlorhexidine-di- [N-hydroxyethyl-ethylenediamine-triacetateJ

(Abbr .: Chlorhex / 2 HEDTA).

The bis-biguanide salts according to the invention can be used in a manner known per se They can be prepared, for example, by the direct reaction of an acid and a base or by them can be obtained by double reaction with another salt of the acid and another salt of the base.

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If the reaction is carried out by direct reaction of a bis-biguanide or its salt in an aqueous medium with a suitable Aminocarboxylic acid or its salt takes place, the reaction preferably carried out in the presence of a readily water-miscible solvent, since the aminocarboxylic acids and their Although salts are generally readily soluble in water, the bisbiguanides and their salts are generally only poorly are water soluble. Suitable solvents are alkanols, in particular methanol and ethanol, so that the reaction preferably carried out in aqueous methanol or aqueous ethanol will.

Both the bis-biguanide and the aminocarboxylic acid can be used for implementation be dissolved in the aqueous alcohol, if necessary, the bis-biguanide can also be dissolved in alcohol and mixed with the aqueous solution of the aminocarboxylic acid are mixed.

The double reaction of salts of the bis-biguanides and the aminocarboxylic acids is preferably carried out using salts of organic acids such as, for example, the diacetate, the bis-biguanides and using alkali salts, for example the sodium salts _. the aminocarboxylic acids carried out. The use of mineral acid salts of bis-biguanide should be avoided y since these salts are very sparingly soluble in water.

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- ίο -

The salts formed can be isolated in a manner known per se. For certain uses, the insulation is not necessary, since the prepared solutions can be used as such.

The bis-biguanide salts of the invention are useful as sequestering agents usable. However, their particular utility is due to the fact that they are excellent antibacterial Have properties. It is known that the salts of bis-biguanide bases show antibacterial activities; the invention However, bis-biguanide salts have a significantly higher antibacterial activity in various respects. For example, the range of activities of the bis-biguanide be broadened at a certain concentration, that is, that at a given concentration previously known bisbiguanide salts are ineffective against a certain type of bacteria, while the corresponding bis-biguanide salts according to the invention, when used in the appropriate concentration, are calculated on the bis-biguanide base, show excellent activity. It can also be used, for example, to kill a bacterial culture required amount of a bis-biguanide salt, if necessary, by using the bis-biguanide salts according to the invention be reduced. In addition, the bis-biguanide salts according to the invention prove to be in comparison with all known salts

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of the bis-biguanide bases as being much more soluble in water, so that much more concentrated solutions can be made.

The bis-biguanide salts according to the invention are preferably incorporated into a suitable carrier prior to use. Naturally the carriers used must under no circumstances have any harmful or toxic effects. The selection. More suitable Carrier media and the processing of the bisbiguanide salts according to the invention are within the range of a pharmaceutical's ability Technologists.

The type of carrier and the type of use of the invention Salts depend on the purpose for which the compounds are to be used; the main use of the compounds is used as a disinfectant, especially in hospitals. Disinfectants are mostly used in solution, water, for example, can be used as a carrier. The bis-biguanide salts according to the invention can, however not only used in medicine, but also in all areas in which bactericidal compounds are required, such as in the feed trade or for preservation.

The compounds according to the invention can not only be used as disinfectants for inanimate objects such as sheets, walls,

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Tables, pots, etc .; that is, furnishings and equipment but are also suitable as antiseptics for treating humans and animals. The invention Bis-biguanide salts can be used orally, perlingually, or externally for this purpose or applied rectally; in these cases, the carrier is preferably used:

a) for tablets, coated tablets, sublingual tablets or

Pills mostly, digestible base masses; for capsules or Cachets digestible push-fit capsules, for powder, powdery solid digestible carriers and for syrups, solutions, suspensions or elixirs digestible liquid media;

b) for ointments, pastes, gels, lotions, baths, vaseline ointments, washing lotions, creams, solutions, emulsions or powders corresponding solid or liquid carrier media;

c) suppository bases suitable for suppositories.

For use as antiseptics, the compounds according to the invention can optionally also be administered in a different form.

The pharmaceutical preparations or the isolated salts contain the two reactants, i.e. the bis-biguanide and the aminocarboxylic acid in the corresponding stoichiometric

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Quantities so that, for example, a salt from Chlbrhex / HEDTA the reactants in the molar amounts of 1: 1 and a salt of Chlorhex / 2 HEDTA the reactants in the molar Contains amounts of 1: 2. If necessary, however, preparations can also be produced which contain one of the reactants in "excess", that is to say, contain an additional amount of either the free bis-biguanide or the free aminocarboxylic acid; in some cases an excess, especially of aminocarboxylic acids, appears to have beneficial effects and the bactericidal ones Properties to improve. When using aminocarboxylic acids in an excess of 1/2 mole per mole of the bis-biguanide particularly favorable results are obtained.

The bis-biguanide-aminocarboxylates according to the invention are all anti-bactericidal; however, they differ in the water solubility. A few salts such as Chlorhex / EDTA are only poorly soluble in water, so that only Difficult to produce pure aqueous solutions that contain sufficiently large amounts of the bactericidal compounds, without the need to use a solubilizer. The present invention thus relates to non-liquid aqueous ones Mixtures with a content of mixtures containing sequestering agents that do not contain a solubilizer, and in where the mixtures are not dissolved in water with a concentration of greater than 1,000 ppm without the aid of a solubilizer can be.

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The compounds according to the invention are therefore preferably processed in the form of liquid aqueous concentrates in which relatively large amounts of the compounds, that is, aleo Quantities of more than 1% by weight are present in dissolved form. These concentrates preferably contain a solubilizer for the compounds Quaternary ammonium compounds are used as solubilizers with a particularly beneficial effect, as these themselves have certain bactericidal properties and detergent properties and the concentrates produced in this way containing the two types of compounds have a certain amount Show synergism *

Of the numerous quaternary ammonium compounds (quats) the following compounds are particularly useful:

Compounds of the general formula IV

CH,

(IV)

1 2 Y-N-Y ^

CH,

in which Y is an alkyl group with 8 to 20 carbon atoms, a di-isobutyl-phenoxy-ethoxyethyl or a di-isobutyl-cresoxy-ethoxy-

ethyl group and Y is an aralkyl group, preferably one

Benzyl group, where Y is optionally on the aromatic

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Core can be substituted. Compounds with the "benzalkonium" cation, which is described in the literature as an alkyldimethylbenzylammonium, are preferred, the alkyl group being a coconut alkyl group, that is to say a mixture of alkyl groups with a chain length of C ₁ Q ^- C ₁ Q ^w * ^{e by} i ^s pi ^elswe i ^se lauryl * denotes myristyl groups, etc.; Corresponding compounds are available in the USA under the trade names Hyamine LOX and Hyamine 1622 (the compounds are described as di-isobutyl-cresoxyethoxyethyl-dimethyl-benzyl-ammonium or di-isobutyl-phenoxy- 'ethoxyethyl-dimethyl-benzyl-ammonium). Myristyl-dimethyl-benzyl-ammonium compounds and compounds of the general formula V are also preferred

CH

used, in which Y is an alkyl group with 8 to 18 carbon atoms or an alkylbenzyl group in which the alkyl group has 8 to 20 carbon atoms has, means. Compounds used with preference are cetyl-trimethyl-ammonium compounds such as, for example Bromide known under the generic name "Cetrimide".

It is also possible to use compounds whose cation is the general Formula VI

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CH ₃

L I YN- CH-

(VI)

Ii c
in which Y and Y can be the same or different and each represent an alkyl group with about 8 to 18 carbon atoms, in particular compounds with the didecyldimethylammonium and the dioctyldimethylammonium cation.

Suitable compounds are also those with a cation of the general formula VII

Y ⁷ -

is

(VII)

in which Y is an alkyl group having 8 to 20 carbon atoms and

7 R
Y and Y can be the same or different and each represent a hydroxy-substituted alkyl or hydroxyalkoxyalkyl group, in particular alkyl-dihydroxyethyl-benzylammonium compounds in which the alkyl group is present, for example, as a coconut alkyl group.

Compounds with the cation of the general can also be used Formula VIII

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(VIII)

in which Y is an alkyl group with 8 to 20 carbon atoms, in particular Compounds with the cetylpyridium cation.

Preference is given to using compounds in which the quaternary. Ammonium cation as benzalkonium, myristyl-dimethyl-benzylammonium, Cetyl trimethyl ammonium or coconut alkyl dihydroxyethyl benzyl ammonium is present.

Those associated with the respective quaternary ammonium cations Anions do not seem to have any influence; usually the hydroxides, chlorides and bromides are preferred.

The amounts in which the quaternary ammonium compound is used as a solubilizer depend on the particular one used quaternary ammonium salt, the bis-biguanide part and the Aminocarboxylic acid content of the salts according to the invention. Quaternaries Ammonium compounds with pronounced solubilizing properties such as cetrimide (cetyl-trimethylammonium bromide) can bring the bis-biguanide salts according to the invention into solution in such amounts that a 20 wt aqueous solution of the active ingredients results, and that the solubilizer solubilizes approximately equal amounts by weight of the compounds, with lower concentrations; of the invention For example, salt this quaternary compound more than its own weight puts into solution. Quarterly connection part,

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received on.

with less pronounced properties can be used to manufacture of about 5 # solutions of the compounds according to the invention can be used, at these concentrations the quaternary compounds convert only about 1/10 of their own weight of salts according to the invention into solution.

Some examples of the maximum amount of various bis-biguanide salts according to the invention that can be dissolved are given below indicated using various quaternary ammonium compounds, the percentages referring to the Relate weight of the finished concentrate solution and the so produced Concentrates are stable:

18 % Cetrimide dissolve 27 % Chlorhex / HEDTA; 30 % benzalkonium chloride dissolves 15 % Chlorhex / HEDTA; 20 % benzalkonium bromide dissolve'20 % Chlorhex / HEDTA;

30 % dodecyl dimethyl ammonium ethosulphate dissolves 30 % Chlorhex / HEDTA;

20 % Cetrimide dissolves 30 % Chlorhex / NTA; 25 % Cetrimide dissolve 5 % Chlorhex / EDTA; 20 % Cetrimide dissolves 30 % (3 Chlorhex / 2 DTPA).

In all cases the maximum solubility of a given Determine bis-biguanide salt in simple experiments using a specific quat.

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As already stated, quaternary ammonium compounds are used as solubilizers in particular because they not only have bactericidal properties themselves, but there is a synergism between the quaternary compounds and the bis-biguanide salts according to the invention appear to exist. The bactericidal activity is greater and in some. Cases considerable greater than the sum of the effectiveness of the two components.

Antiseptics and disinfectants can be added in a simple manner by mixing the salts with the carrier and optionally an excess of bis-biguanide or aminocarboxylic acid and / or quaternary ammonium compounds are produced. The invention Salts do not necessarily need to be isolated from the conversion solution, but the conversion solution can already find use as an aqueous carrier.

The production of disinfectants can be done in the simplest way or antiseptics are therefore made by dissolving the bis-biguanide and the aminocarboxylic acid in water or aqueous alkanol and this solution is then optionally mixed with a quaternary ammonium compound.

Since the quaternary ammonium compounds for salt formation with the aminocarboxylic acids are capable, can optionally also

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the bis-biguanide can be dissolved in water or aqueous alkanol, whereupon the salt of a quaternary ammonium compound and an aminocarboxylic acid is added. The following Examples are intended to explain the invention in more detail. The first examples show the preparation of the bis-biguanide salts according to the invention described.

example 1 MoncK chlorhexidine) mono- (ethylenediamine tetraacetate)

0.625 g (0.001 mol) of chlorhexidine diacetate was dissolved in 25 ml of distilled water and made into a solution of 0.336 g (0.001 mol) disodium ethylenediamine tetraacetate in 10 ml of distilled water was added. A fine white color was formed in the process Precipitate which was filtered off, washed with distilled water and dried. Mono- (chlorhexidine) -mono- (ethylenediamine tetraacetate) had a melting point of 235.degree. The salt contains one mole of chlorhexidine and one mole of EDTA.

In order to determine that salt had actually formed, comparative tests were made against the possibly present Mixtures carried out. Chemically it could be demonstrated that the precipitated compound was neither sodium nor acetate ions, but Contained chlorhexidine and EDTA ions. The melting point of chlorhexidine is 127 ° C, the melting point of EDTA is

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at 242 C and a mixed melting point of equal proportions of the compounds gave a value of 215 C.

DSC analyzes (differential scanning calorimeter) also showed that a salt was present.

The water solubility of this salt is relatively low and is about ^{0.02% by weight in water at 20 °} C. For a more precise determination of the solubility, samples of the salt with a weight of 0.01, 0.02 and 0.03 g were used weighed out in beakers and admixed with 100 g of distilled water. These mixtures were then heated to 100 ° C. with stirring, the solutions were made up to 100 g with water in order to compensate for evaporation losses, and then cooled to room temperature. A small seed crystal of the salt was then added and, after 2 hours, the mixtures were checked for complete solubility. The test in which no visible residue was left behind was designated as complete solubility. In this type of determination, the solubility in water was determined to be 0.02% by weight at 20 ^° C. .

Example 2 . . . .

Mono-chlorhexidine) -mono- (hydroxy'ithyl-ethyiendiamine-triacetate)

Method a

2.66 g of chlorhexidine base and 1, ^ O g of hydroxyethyl-ethylenediamine triacetic acid were dissolved together in 50 ml of distilled water with heating. The acid and the base were present in approximately equimolar amounts in the solution. The solution was then cooled and a white precipitate formed after a few hours. The precipitate was filtered off, washed and dried. The pH of the mother liquor was 7-3. The melting point of mono- (chlorhexidine) -mono- (hydroxyäthy1-ethylenediamine triacetate) was 173 ° C; Using the method described in Example 1, the solubility in water was determined to be 0.2 % by volume at 20 ° C.

Method B.

25 ml of a 0.01 M solution of chlorhexidine in methanol (corresponding to 0.1263 g of chlorhexidine) were added to a solution of Added 0.0695 g of HEDTA in 35 ml of distilled water. The one containing the acid and the base in approximately equimolar amounts Solution was concentrated in half on the water bath and then slowly cooled. After standing for about 2 hours, the Crystallization initiated by scratching with a glass rod ;; the resulting precipitate was filtered off and dried.

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Method c

1 g of chlorhexidine diacetate was dissolved in 25 ml with methyl alcohol Denatured industrial fuel dissolved and with a solution of 0, ^ 448 g HEDTA dissolved in 3.2 ml of 1 N NAOH and 5 ml of distilled water. From the one containing the acid and the base in equimolar amounts A precipitate separated out on standing solution and was filtered off, washed with distilled water and dried.

The DSC analysis showed that salt formation occurred in each case was. This fact also emerged from the comparison of the melting points:

Melting points · ■

HEDTA 156 ° C Chlorhexidines . 127 ° C Salt according to methods A and B. 173 ° C Method C salt 177 ° C

physical mixture of acid and base

Example 3 Mono- (chlorhexidine) -di-hydroxyethyl-ethylenediamine-triacetate)

1.33 g of chlorhexidine and 1.2 g of HEDTA were mixed together with heating dissolved in 25 ml of distilled water so that the molar

Ratio of Rase to Acid was 2: 1. The solution then became

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cooled to form a white precipitate which was filtered off, washed and dried. The pH of the mother liquor was 6.1. Mono (chlorhexidine) di (hydroxyäthyläthylendiamin triacetate) had a melting point of 172 ⁰ C and determining in the manner described in Example 1 Method a water solubility of 0.3 wt.% At 20 ⁰ C.

example Mono- (chlorhexidine) -mono- (nitrilotriacetate)

25 ml of a 0.04 M solution of chlorhexidine diacetate in distilled water was added to 25 ml of a 0.04 M solution of disodium nitrilotriacetate in distilled water. The solution thus contained the acid and the base in equimolar amounts. A fine oily precipitate that formed solidified on standing, this precipitate was then filtered off, washed with distilled water and dried. Mono (chlorhexidine) mono- (nitrilotriacetate) gave a water solubility of 0.3 wt. At 20 ⁰ C when the determination was carried out according to the method described in Example 1.

The DSC analysis confirmed the salt formation, which was also reflected by Comparison of the melting points revealed:

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Melting points

NTA, 225 ° C

Chlorhexidine 127 ° C

Salt 176 ° C

physical mixture of.NTA

and chlorhexidine 129 C

Example 5 Tri- (chlorhexidine) -di (diethylene-triamine-pentaacetate)

0.69 g of diethylenetriamine pentaacetic acid were dissolved in 100 ml of distilled water with heating. 1> 33 g of chlorhexidines were dissolved in this solution with heating and stirring, so that the molar ratio of base to acid was 3: 2. An oil precipitated out on cooling, but this changed after standing for 2 days. Solidified to white crystals at room temperature. The crystals were recrystallized from water and then dried at 100 ° C. to constant weight. Tri- (chlorhexidine) di (diethylenetriamine pentaacetate) had a melting point of 157 ⁰ C and a solubility in water when measured by the method described in Example 1 of 0.2 weight on.% At 20 ⁰ C.

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Example 6 Mono- (chlorhexidine) -di (dihydroxyäthy1-aminoacetat)

100 ml of a 2 # solution of chlorhexidine diacetate in distilled water were added to a solution of 1.23 ¹ l g of the monosodium salt of dihydroxyethyl-aminoacetic acid (corresponding to 1.0432 g of dihydroxyethyl-aminoacetic acid) in distilled water, so that the molar The ratio of chlorhexidine cations to dihydroxyethyl aminoacetate anions was 1: 2. The precipitate which formed was filtered off, washed and dried. Mono (chlorhexidine) di (dihydroxyäthylaminoacetat) had a water solubility of 0.2 wt.% At 20 ⁰ C when determined by the method described in Example 1 method.

The DSC analysis confirmed the salt formation, which was also found in Comparison of the melting points showed:

Melting points 180 ° C Dihydroxyethyl amino acetic acid 12? ° C Chlorhexidines 86 ° C salt 107 ° C physical mix of
Acid and base

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Example 7 Mono- (picloxidine) -mono- (ethylenediamine tetraacetate)

25 ml of a 0.02 M solution of disodium ethylenediamine tetraacetate in distilled water were mixed with 25 ml of a 0.02 M solution of picoloxidine diacetate in distilled water, so that
the picloxidine cation and the EDTA anion were present in equimolar amounts. The precipitate was filtered off, washed with distilled water and dried. Mono (piclöxidine) mono- (ethylene diamine tetraacetate ·) had a solubility in water of less than 0.01 wt.% At 20 ° C for carrying out the method described in Example 1. The DSC analysis confirmed the salt formation as
also results from a comparison of the melting points:

Melting points

EDTA

Piclöxidine 219 ° C

Salt 230 ° C

physical mixture 2l8 ° C

Example 8 '■

Mono- [l, 6-.biS "(N _:. -P-methylthiophenylguanido-N _c - ) -hexane] -mono- (hydroxyethyl-ethylenediamine-triacetate)

Equimolar amounts of the biguanide base and of the hydroxyethyl-ethylehdiarnin-triesfdgijiiure were dissolved in distilled water. the

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Solution was then concentrated almost to dryness and crystals formed on standing. The crystals were filtered off, washed and dried. When measured according to the method described in Example 1, the water solubility of the mono-jj., 6-bis- (N ₁ -p-methylthiopheny lguanido-N, -) -hexanj-mono- (hydroxyethylethylenediamine triacetate) of 0 was found , 2 wt.% at 20 ⁰ C.

DSC analysis confirmed the salt formation, as can be allowed to determine by comparison of the melting points, since the melting point of the salt 25 ¹ I ⁰ C, the melting point of Biguanidbase 251 ° C, .the melting point of HEDTA 156 ° C and the mixed melting point of a physical mixture of acid and base was 226 ° C.

Example 9 Mono- (pieloxidine) -mono- (nitrilotriacetate)

25 ml of a 0.04 M solution of picloxidine diacetate in distilled Water was added to 25 ml of a 0.04 M solution of disodium nitrilotriacetate added in distilled water so that the molar ratio of picloxidine cations and nitrilotriacetate anions was the same. The precipitate which formed was filtered off, washed with distilled water and dried. at The determination according to Example 1 was carried out for mono-

209851/1236

(Picloxidine) -mono- (nitrilotriacetate) a water solubility of 0.2 wt. % at 20 ⁰ C found.

The DSC analysis also confirmed the salt formation. A comparison the melting points gave the following values:

Melting points

NTA 225 ° C.

Picloxidine 219 ° C

Salt 220 ⁰ C

physical mix of

Base and acid. 201 C

Example 10 Mono- (pieloxidine) -di (dihydroxyethyl ~ aminoacetate)

100 ml of a 2% solution of Pieloxidine diacetate in distilled Water were added to a solution of 1.178 g of the monosodium salt of dihydroxyethyl-aminoacetic acid in distilled water added (corresponding to 0.993 g of dihydroxyethyl-aminoacetic acid). The ratio of picloxidine cations to dihydroxyethyl aminoacetate anions was between 1: 1 and 1: 2. The precipitate which formed was filtered off, washed and dried. That . formed Mono-CpicloxidineJ-di-idihydroxyethyl-aminoacetate) when measured according to the method described in Example 1

2 09 851/1236

a Wasserlöalichkeit of 0.2 wt.% at 20 ⁰ C.

The salt formation was determined by the DSC analysis and by the Melting points confirmed:

Melting points 180 ° C Dihydroxyethylaminoacetic acid 219 ° C Picloxidine 227 ° C salt 165 ° C physical mix of
Acid and base

Example 11 Mono- (picloxidine) -mono- (diethylenetriamine-pentaacetate)

25 ml of a Ο, ΟΊ M solution of disodium diethylenetriamine pentaacetate in distilled water were mixed with 25 ml of a 0.0 * 1 M solution of picloxidine diacetate in distilled water. The picloxidine cations and the DTPA anions were therefore present in equimolar amounts. The precipitate that formed was filtered off, washed with distilled water and dried. Mono (picloxidine) mono- (diethylenetriamine pentaacetate) afforded when measured by the method described in Example 1 a water solubility of 0.2 wt.% At 20 ⁰ C.

2 0 9 8 51/1236

at U ^ P

The salt formation was confirmed by comparing the melting points:

Melting points

DTPA 215 ° C

Picloxidine 219 ° C

Salt 190 ⁰ C

physical mix of

DTPA and Base 192 C

In the following examples the use of the inventive Compounds described as bactericides in disinfectants without the addition of quats.

Example 12

Solid mono- (chlorhexidine) di (hydroxyethyl-ethylenediamine triacetate) prepared according to Example 3 was dissolved in hard standard water according to W.H.0.-regulation, so that solutions with a content of 400, 600, 8OO, 1,200, 1,600, 2,000 and 2,500 ppm of the connection.

Bacteriological experiments

These solutions were tested for bactericidal activity according to British Standard No. 3286: i960 (described in "Method for

209851/1 236,

laboratory evaluation of disinfectant activity of quaternary ammonium compounds by suspension test procedure ", British Standard Institution, British Standards House, 2 Park Street, Londen, S.W. 1 London, 1960). Since numerous antibacterial mixtures against gram-negative bacteria are less are effective as against gram-positive bacteria and have bactericidal activity in the presence of hard water and / or organic Matter such as blood serum is degraded against Pseudomonas pyocyanea, a highly resistant one gram-negative bacterium, carried out in the presence of hard water Test particularly tightened.

The main test conditions are as follows:

(i) Nutrient medium Nutrient broth No. 2 contains:

Lab-lemco (proteinaceous material) 10 g

Peptone 10 g

Sodium chloride 5g

distilled water ad 1,000 ml

The solution is autoclaved at 121 ° C. for 15 minutes. The pH is about 7> 4.

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^efn » ^g ! ^nam - ^ - ^^ 223766

Inactivator

Nutrient broth with the addition of IO % Lubrol W. (trademark of a

Condensation product of a long-chain fatty alcohol and

Ethylene oxide).

Standard hard water (W.H.0 regulation)

10 J solution of CaCl ₃ .6H ₃ O (weight / volume) 17.5 ml 10 % solution of Mg 30 ^ .7HpO (weight / volume) 5.0 ml distilled water. 3,300 ml

This solution is autοclaviert 15 minutes at 121 ⁰ C. Disinfection time 5 minutes.

Temperature 22 ° C.

Test germ Pseudomohas aeruginosa (Pseudomonas pyocyanea) NCTC No. 6 '

Added organic matter 10 % bovine serum.

(ii) Preparation of the culture

An agar culture of the germs was produced in the nutrient broth and incubated for Zk hours at 37 ° C. Ee became daily subcultures

209851/1236

further bred and the cultures between the 3rd and 7th generation used for the test. The nutrient broth culture of Pseudomonas Pyocyanea was aseptically filtered or the broth was shaken before use, 15 minutes to settle and the supernatant liquid used for the test.

Dilution of the culture

A portion of the nutrient broth culture was diluted with 2 * f parts of standard hard water in which ¹ J of the culture broth to 96 ml ml of standard hard water was added. The average number of germs in this dilution is 5 x 10 germs per ml,

Test method

A series of double dilutions of the antibacterial mixtures to be tested were made in standard hard water and filled each 2.5 ml into a sterile test tube. (A series of double dilutions is understood to mean that for example, if a compound is to be tested at a concentration of 500 ppm, a solution at a concentration of 1,000 ppm must be made, since the volume of this solution is diluted twice again.) Each Test tube with the antibacterially active substance to be examined

ι solution was then at the zero time of the test with 2.5 ml of the diluted bacterial culture added, the total mixture was adjusted so that it had a hardness of 300 ppm. After 5 minutes, 1 ml of the mixture was removed from each test tube

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- 35 - '2225766

transferred to a sterile test tube with 9 ml of inactivator. 1 ml this mixture was then transferred to an agar plate and a another ml was added to a second test tube with 9 ml of the inactivator convicted. Correspondingly, 1 ml of the mixture was again transferred to an agar plate after the second treatment with the inactivator and another ml in a third test tube with 9 ml of the inactivator transfer. The inactivator cancels the effect of the antibacterial agent, so that any living Bacterium can form a colony on the agar plate. After 48 hours Incubation at 37 C, the number of colonies on each plate is counted with the appropriate dilution factor multiplied and the results are expressed as the number of surviving germs per million inoculated bacteria. As-reference a culture without an antibacterial additive v_e.r is used > Undiluted this results in a germ count of about 2.5x10 'bacteria per ml.

Control experiments were made using chlorhexidine dihydrochloride and chlorhexidine digluconate carried out to show the superiority of the compounds according to the invention, and to to serve as standards for the test conditions, and for the resistance of the germs.

Results

In the following Table I the results are given as the number of surviving germs immediately after adding the inactivator, ' based on one: 'Million inoculated bacteria ", -listed. ■

209 85 T / 12 3 6 ''

Table 1

Concentration of the compound in ppm 200 300 l | 00 600 800 1000 1250

Bactericidal

Mono- (chlorhexidine) -di (HEDTA) 21,818 2,909

Chlorhexidine dihydrochloride (control)

u / c u / c

Chlorhexidine digluconate (control) u / c

u / c u / c

- insoluble u / c 3.627

u / c - number of surviving germs too large to count.

The results clearly show that mono- (chlorhexidine) -di (HEDTA) In much smaller amounts than chlorhexidine dihydrochloride or chlorhexidine digluconate must be used to make a given Kill amount of Pseudomonas pyocyanea.

Example 13

Solid mono- (chlorhexidine) -mono- (hydroxyethyl-ethylenediamine triacetate) prepared according to Example 2 became solutions with a Content of 400, 800, 1,200, 1,600 and 2,000 ppm processed.

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Bacteriological test

These solutions were tested for their bactericidal activity as described in Example 12. Control tests were carried out in same concentrations of chlorhexidine diglueonate solutions are used. The results are shown in Table II.

Table II

Concentration of

Compound in ppm 200 400 600 800 1000

Bactericide mono- (chlorhexidine) -

mono- (HEDTA) 390 0 0 0 0

Chlorhexidine

digluconate (control) - - 300 5Ü0 26

From the table it can be seen that the bactericidal properties of mono- (chlorhexidine) -mono- (HEDTA) are much more pronounced than those of chlorhexidine digluconate.

Example 14

Solid mono- (chlorhexidine) -mono- (nitrilo-triacetate) prepared according to Example 4 became solutions with a content of dissolved at 400, 800, 1,200, 1,600 and 2,000 ppm,

20-9851 / 1236-

2723766

Bacteriological studies

The solutions were according to that described in Example 12
Way tested for their bactericidal activity. A solution with the same concentration of chlorhexidine digluconate was used as a control. The results are shown in Table III.

Table III

Concentration of

Compounds in ppm 200 400 600 800 1000

Bactericidal

Mono- (chlorhexidine) -

mono- (nitrilotriacetate) 10,000 235 Q 0.

Chlorhexidine

digluconate (control) - - 300 5 ^ 0

The table shows that mono- (chlorhexidine) -mono- (nitrilotriacetate) in comparison to chlorhexidine digluconate has a much stronger bactericidal effect.

Example 15

Solid tri- (chlorhexidine) -di (diethylenetriamine-pentaacetate) prepared according to Example 5 was made using

0 9 8 51/12 3

hard standard water to solutions with a content of ¹ 100, 800, 1,200, 1,600 and 2,000 ppm.

Bacteriological studies

These solutions were tested for their bacteriological activity in the manner described in Example 12, using as Control compounds chlorhexidine digluconate was used in equal concentrations. The results are shown in Table IV. '

Concentration of
Compounds in ppm

Table IV

200

4 00

600

800

1000

Bactericidal

Tri- (chlorhexidine) -di (DTPA)

Chlorhexidine digluconate (control)

u / c

2636

133

u / c

0 '318

The table shows that tri- (chlorhexidine) -di (diethylenetriamine-pentaacetate) has much stronger bactericidal properties.

Example 16

Solid mono- (chlorhexidine) di (hydroxyethyl aminoacetate) prepared according to Example 6 was made using hard

20985 1 / 123G.

Standard water (W.H.O. regulation) to solutions with a content at 800, 1,200, 1,600 and 2,000 ppm.

Bacteriological studies

The solutions were tested for their bactericidal activity in the manner described in Example 12, using as a control Chlorhexidine digluconate was used in equal concentrations. The results are shown in Table V.

Table V

Concentration of

Compounds in ppm 400 600 800 1000

Bactericidal

Mono- (chlorhexidine) -

di- (hydroxyethylaminoacetate) 600 35 0 0

Chlorhexidine digluconate (control) - 1200 520 308

The table shows that ¹ that mono- (chlorhexidine) di (hydroxyethyl-aminoacetate) has a much stronger bactericidal effect than chlorhexidine digluconate.

Example 17

Solid mono- (picloxidine) prepared according to Example 9 mono- (nitrilotriacetate) was made using hard

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Standard water (W.H.O. regulation) to solutions with a content dissolved at 1,600 and 2,000 ppm.

Bacteriological studies

The solutions were examined for their bactericidal activity as described in Example 12. The results are shown in the table VI listed.

Table VI

Concentration of mono- (chlorhexidines) -

mono- (NTA) in ppm 80Q 1000 ■

surviving germs per ml / 1 million germs 10,000 1900

These results show that mono- (chlorhexidine) -inoao- (nitrilotriacetate) is a bactericidal compound.

Example 18

Mono- (picloxidine) -mono- (hydroxyethyl-ethylenediamine-triacetate) became solutions in standard hard water (W.H.0 prescription) with a content of 1,600 and 2,000 ppm.

Bacteriological studies

The solutions were tested in the manner described in Example 12 for their bactericidal activity. The results are in Table VII listed.

2Q03S1 / 1236

β ν:

en am u.cyL · 22237B6

Table VII

Concentration of mono-

(picloxidine) -mono- (HEETA) in ppm 800 1000

surviving germs per ml / 1 million germs 5400 640

The table shows that mono- (picloxidine) -mono- (hydroxyethyl-ethylenediamine-triacetate) is bactericidal,

In the following examples the use of the inventive Bis-biguanide salts in disinfectants with additives of quaternary ammonium compounds.

Example 19 Making the solution

14.3 g of chlorhexidine, 20.4 g of cetyltriethylammonium bromide and 7.8 g of hydroxyethylethylenediamine triacetic acid (HEDTA) were
reacted with stirring in 57.5 g of water until a clear solution was formed, which was dilutable with water in all concentrations and a mixture of mono- (chlorhexidine) -mono- (hydroxyathy1-ethylenediamine triacetate) and cetyl-trimethylammonium bromide contained.

Bacteriological examinations (antiseptic test)

The solution produced was examined for its bactericidal activity in accordance with a modification of the British Standard Specification 2HS2

2 0 9 8 5 1/12 3 6

Stricter test consists in that, as already stated, the highly resistant gram-negative bacterium Pseudomonas pyocyanea is used as a test germ in the presence of hard water and organic material. The test conditions are as follows:

(i) Nutrient Broth As in Example 12, Nutrient Broth No. 2 was used.

Inactivator .

Nutrient broth with the addition of 0.5 % lecithin ex ovo (lecithin from egg yolk, a compound of choline, glycerine, phosphoric acid and various fatty acids) and 2 % Lubrol W (trademark of an anhydrous condensation product made from a long-chain petroleum alcohol and ethylene oxide). The pH will be if
necessary, set to 7> 2.

Test germ

Pseudomonas aeruginosa (pyocyanea) N.C..T.C. No. 67 * 19 on nutrient held agar.

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(ii) Making the culture

An agar culture of the test germs is set up in the nutrient broth and incubated at 37 ° C. for 24 hours. It becomes daily subcultures cultivated further, and the cultures between the third and seventh generation used for the test. The nutrient broth culture of Pseudomonas pyocyanea is aseptically filtered or shaken before use, 15 minutes to settle and used the supernatant liquid for the experiment.

Culture dilution

One part of the nutrient broth culture is diluted with 2k parts of distilled water or k ml of the culture + 96 ml of distilled water. In this dilution, the average number of germs is 5 x 10 'germs per ml.

Test method

A double dilution series of the antibacterial mixture to be tested was made with distilled water, then 2.5 ml each were poured into sterile test tubes. At the zero time of the experiments, 2.5 ml of the diluted bacterial culture suspensions with a content of 20 % bovine

20985 1/1236

serum in each test tube with the dilution of the antibacterial effective solution filled. After 5 minutes, a platinum loop, corresponding to about 0.01 ml, was removed from each test tube. a part of the mixture in 10 ml of the nutrient medium mixed with the inactivator in -a series of new sterile reagent- ' inoculated glasses. After a total of 10 minutes, another part was transferred to further test tubes with inactivator using the loop and nutrient medium inoculated. The effect of the antibacterial agent is canceled by the inactivator, see above that the bacteria can grow again. All test tubes inoculated with the aid of the loop were kept at 37 ° C. for 48 hours incubated and then checked for the resulting bacterial growth. The result was rated as positive if growth had taken place and negative if no growth had taken place would have. The lowest concentration of the antibacterial agent that gives a negative result after a 5-minute contact, which is confirmed by the 10-minute contact. is required, is referred to as the killing dilution of the bactericidal. The contents of the test tubes with a negative result was subcultured in nutrient broth to ensure that the bacteria were actually killed, and that not only one bacterial stasis had occurred *

The results are expressed as the minimum concentration which results in 5 minutes at 22 ⁰ C to to a 100% kill.

The average of various experiments with benzalkonium chloride

- 46 - 2273766

B.P.C. resulted in the following values, for example:

Dilution inoculation in minutes

5 '.10

1-666 = 1,500 ppm ->

1-1000-1000 ppm +

1-1333 = 750 ppm + -.

1-2000 = 500 ppm ++

The concentration causing a 100 # kill is 1500 ppm. Due to statistical fluctuations, the exact Concentrations between about 1000 and 1500 ppm are, it follows that the killing concentrations in the following tests are subject to statistical fluctuations of this order of magnitude.

Since the concentrations of the various salts are according to the examples and expressed as ppm total organic compound, d. H. Bis-biguanide + quaternary ammonium compound + Let aminocarboxylic acid be determined and therefore the relative Quantities of the individual components are known, can be seen from the The results of the antiseptic tests show the killing dilution for bis-biguanide salts and / or quaternary ammonium compounds to calculate.

Results

The results of the tests are shown in Table VIII.

The kill dilutions are used as control compounds Chlorhexidine digluconate and for a typical quaternary ammonium salt with a sequestering agent, namely mono- (myristyl-dimethyl-benzyl-ammonium) -mono (HEDTA) also listed «

Table VIII
Kill dilutions

Bactericidal (a) ppm Bis- (b) ppm Quat (c) ppm ppm orgabigüanid (Cation + acid niche

Anion) bond

Mix of

Example 19 60 90 30 l80

Chlorhexidine

²⁰ ° - «0 350

Sequestering Agent - 1060 HHO 1500 (Control)

The table shows that the antiseptics according to the invention much more bactericidal than chlorhexidine digluconate and the quat compound.

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Example 20:

42.1 g of a 29.2% strength by weight solution of benzalkonium hydroxide were added to 4.38 g of ethylenediamine-tetraacetic acid (EDTA). The mixture was then on
diluted a total volume of 97 ml, and g 0, ^1, J-resistant
Chlorhexidine added. This mixture formed a clear,
aqueous solution.

Example 21;

A solution of 12.6 g of chlorhexidine, 18.8 g of cetyl trimethylammonium bromide and 9.2 g of hydroxyethyl-ethylenediamine-triacetic acid in 300 g of water were heated to 60 ° C. and stirred mixed with 8 parts of glycerin. A completely gelatinized mixture was obtained, for example for application suitable for the skin.

Example 22 :

From 17.6 g of chlorhexidine, 18.2 g of cetyl trimethyl ammonium bromide and 11.2 g of hydroxyethyl-ethylenediamine-triacetic acid were prepared in 53 g of water, a clear, aqueous solution.

Bacteriological studies

This solution was, as described in Example 19, on their

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■ - 49

investigated bactericidal effectiveness. The results are shown in Table IX.

Table IX Kill Dilution

Bactericidal a) ppm Bis- b) ppm Quat c) ppm ppm organic biguanide base acid compounds

Mix of

Example 22

a) 75 75 ^ 5 195

Comparing these results with those listed in Table VIII Results for chlorhexidine digluconate and the quat sequestrate clearly show that the compounds according to the invention have much better bactericidal effects.

Example 23:

15 g of the di ~ (myristyl-dimethyl * benzyl) ammonium salt of HEDTA and 8 grams of chlorhexidines were dissolved in 77 grams of water to give a clear solution.

Bacteriological studies

This solution was tested according to Example 19 ₃ with the in

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Results listed in Table X were obtained.

Table X

Killing thinner

Bactericidal (a) ppm Bis- (b) ppm Quat (c) ppm ppm organic biguanidic acid compounds

Base (a) + (b) + (c)

Mix of

Example 23 53 71 29 153

Compared to chlorhexidine digluconate and the quat sequestrate from Table VIII, this shows the clear superiority the mixture according to the invention.

example 2k

367 * 5 S (1 mol) of myristyl-dimethyl-benzyl-ammonium chloride were dissolved in the smallest possible amount of isopropyl alcohol. A saturated solution of 56 g (1 mol) of potassium hydroxide in absolute ethanol was added to this solution while stirring. After a few hours a precipitate of potassium chloride precipitated out, which was filtered off and washed with isopropyl alcohol. The washing liquid was combined again with the mother liquor, which is an alcoholic solution of myristyl dimethyl benzyl ammonium hydroxide. This solution was divided into 10 equal parts, each 0.1 mol, corresponding to 3 ^; J ₃ 9 ß »of the quaternary animo-

2 0 9 8 5 1/12 3 6

contained sodium hydroxide. .

For the preparation of a 15% strength by weight aqueous solution of the di- (myristyl-dimethyl-benzyl-ammonium) salt the EDTA were 1Ί, 6 g (0.05 mol) of solid ethylenediamine-tetraacetic acid in warm water dissolved and then with an aliquot of the solution of myristyl-dimethyl-benzyl-ammonium hydroxide prepared as described mixed. This solution contains after dilution to 318 ml 47.7 g (0.05 mol) of the di (myristyl-dimethyl-benzyl-ammonium) salt the EDTA. . .

100 ml of this 15 ^ solution with a content of 15 g of di- (myristyl-dimethyl-benzyl-ammonium) -ethylene-diamine-tetraacetate, corresponding to 10.4 * 1 g of the quatkation and 4.56 g of the dibasic EDTA anion has a molar ratio of quat cation to EDTA anion of 2: 1.

Since the molecular weight of the chlorhexidine base is 505, the required amount of chlorhexidine is used to produce the chlorhexidine salt from one mole of chlorhexidine and 2 moles of EDTA calculated by taking the 15 g of the Quat-Sequestrans salt with a content of M, 56 g of the dibasic anion accordingly

χ 4.56 = 4.12 g chlorhexidine can be converted.

2 ml of the 15 % i & en solution of the di- (myristyl-dimethyl-benzyl-

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ammonium) -äthylen-diamine tetraaeetat are thus at jio offset ⁰ C with 0.08 g Chlorhexidine, forming a clear solution, then withdraw from the on cooling crystals.

Example 25:

According to the ^{method described in Example 2 1} J, the mono- (myristyl-dimethyl-benzyl-ammonium) salt of hydroxyethyl-ethylenediamine-triacetic acid was prepared by adding an aliquot containing 0.1 mol of myristyl-dimethylbenzyl-ammonium hydroxide 27 » 8 g (0.1 mol) of a solution of HEDTA in water were added and then made up to 418 ml. This 15 wt. / S solution contains 8.18 % of the quaternary ammonium cation and 6.82 % of the monobasic HEDTA anion. To prepare the mono- (chlorhexidine) di (HEDTA) salt, the amount required is calculated by calculating the molar weight ratio of 505 parts of chlorhexidine to 2 278 parts of HEDTA, calculated as the free acid, or 2 277 parts as a monobasic anion, is determined. Accordingly, 0.12 ¹ I g of chlorhexidine in 2 ml of the 15 # solution of the mono- (myristyl-dimethyl-benzyl-ammonium) -mono- (HEDTA) -salt to form a clear solution of the mono- (chlorhexidine) -di (hydroxyethyl ethylenediamine triacetates) dissolved. This solution can be mixed with distilled water, for example, to a solution with a content of 820 ppm quat cation, 662 ppm monobasic HEDTA-

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Anion and 620 ppm chlorhexidine are diluted. Example 26: ',

According to the method described in Example 24, di- (myristyl-dimethyl-benzyl-aimoniunO-mono-chydroxyethyl-ethylenediamine triacetate) was prepared by adding 0.1 mol of the quaternary ammonium hydroxide and 13.9 g (0.05 mol) of HEDTA 314 ml were dissolved, so that a 15 wt. SS solution with a content of 10.6 % quat cation and 4.4 % of the dibasic HEDTA anion resulted.

2 ml of this 15 # solution were mixed with 0.16 g of chlorhexidine added, so that a molar compound of chlorhexidine with the two-base HEDTA anion was formed, namely mono- (chlorhexidine) -mono- (hydroxyethyl-ethylenediamine-triacetate), This resulting clear solution could be further increased with water be thinned to a content of ΊΟ6Ο ppm quat cation, 440 ppm HEDTÄ ^ anion and 8OO ppm chlorhexidine.

Bacteriological studies.

This solution was _y ausgetestei- on their bactericidal activity after besehriebene.n in Example 19 method wherein as KonferollL · 'compounds Chlorhexidine ^ diglucQnat and di (myristyl, -dim ^ thylbenzy.l-ammonium) mono- (hydr-oxyäthy 1-ethylenediamine triacetate) were used with. The results are given in Table Xa.

Tabel

Xa

Bactericidal

Quatsalz der acid

ppm quat

1500

Killing dilutions

ppm quat- ppm cation HEDTA anion

1060

kko ppm ppm active weight? Chlorine-chlorine constituents + hexidine in
hexidine quat-cation active ingredients

total quantity
org. Compounds in ppm

1060

1500

Mixture example

**> Chlorhexidine · Φ

digluconate

100

71

29

124

200

100

153

350 *

2223761

The table clearly shows the superiority of the compounds according to the invention compared to the salts des quats and dem.chlorhexidine digluconate.

Example 27:

According to the method described in Example 26, Morio (chlorhexidine) di (hydroxyethyl ethylenediamine triacetate) with a molar ratio of chlorhexidine of 1: 2 moles of the HEDTA anion prepared by adding 2 ml of the 15 # solution of di- (myristyl-dimethyl-benzyl-ammonium) -mono- (hydroxyethylethylenediamine triacetate) 0.08 g of chlorhexidine were added to form a clear solution, which was further diluted with water let dilute.

Bacteriological studies

This mixture was, as described in Example 19, on their tested bactericidal activity, the results are summarized in Table XI.

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Table XI

Killing dilution

Bactericidal

ppm Quat- ppm HEDTA- ppm chlorine cation anion hexidine ppm weight % chlorine constituents + hexidine in
Quat cation active ingredients

total quantity
organic compounds in ppm

ro ο cr>

Mixture of example

400 y?

283

117

108

'28

508

This experiment also shows that the mixture according to the invention is much stronger Has bactericidal properties than the salt of the sequestering agent with the quat · or chlorine-J

hexidine digluconate. CD

cn

Example 28:

According to the method described in Example 2β were 15% gene -. By weight solutions of di- (myristyl-dimethyl-benzylammonium) mono- (hydroxyethyl-ethylenediamine-triacetatjmit the free base of Chlorhexidine in quantities _s added to the mixtures of the mono- ( chlorhexidine.) - mono- (HEDTA) -salz and the mono-fchlorhexidine) -di (HEDTA) -salz with excess di-quat-mono- (HEDTA) -salt correspond »

The mono- (chlorhexidine) -mono- (HEDTA) -salz was made from 15 $ solutions of the HEDTA salt of the quat and 8 % chlorhexidine and the mono- (chlorhexidine) -di (HEDTA) -salt was made from 15 ^ -igen quat salt solutions and h% chlorhexidine produced, so that the following mixtures resulted:

a) 15 % Quat-HEDTA + 15? Chlorhexidine (molar ratio below 1: 2)

b) 15 $ Quat-HEDTA + 2 % chlorhexidine (molar ratio below 1: 2) ■.

c) 15 % Quat-HEDTA + 6 % chlorhexidine (molar ratio above 1: 2, but below 1: 1)

BAD OBKaINAL

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Bacteriological studies

M. £ 8s Mischui'JKön were investigated according to Example. '. 9 ^ n ^ her ^ bäK ^ e ri:; lde ^ kvlvit;! T. The result ~ - s ^:; .: id in Tabe-ls XII aui ^j ™ n; t leads.

2 0 9 8 5 1/12 3 6 BAD ORIGINAL

Tabel

XII

Kill dilution

ppm quat ppm quat ppm

Cation HEDTA anion

ppm chlorine- ppm Behexidine components + Quat · * cation

Weight % chlorhexidine in active ingredients

Total amount of organic connections

solution

O CD CO CTt

1000

500

150

707

354

10 β

293

146

44

8.6

1067

16 567 Ul
VO 421 36 210 I. 166

Here, too, it can be seen that the mixture compared to the known bactericides, the quat HEDTA-SaIz 'and chlorhexidine digluconate has significantly better bactericidal properties.

N *

CD

CJ)

Example 29:

A number of mixtures of chlorhexidine-di- (hy ~ hydroxyethyl ethylenediamine triacetate) and didecyl dimethylammonium chloride prepared by directly adding a 0.2% by weight solution of the salt by dissolving 0.954 g of chlorhexidine and 1.046 g of HEDTA was made up in 1000 ml of water. This salt, chlorhexidine-di- (HEDTA) can also be used after the in Example 3 described method can be prepared.

Didecyl-dimethyl-ammonium chloride is commercially available in the form of a concentrated, 50 % aqueous solution. A 0.2% solution of the salt was made up by dissolving 4.0 g of this concentrated solution in 1000 ml of distilled water.

The two solutions were then mixed in the following volumes mixed:

Chlorhexidine-di- (HEDTA)

100 %

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Solution Quat salt A (control) 100 % B. 90 % C. 70 % D. 50 % E. - 30 % P. 10 % G 0

Bacteriological studies

Solutions A to G were examined for their bactericidal activity in the manner described in Example 19, the killing dilution of chlorhexidine digluconate also being determined as a control. The results are in the table
XIII and graphically in fig. I of the drawings.

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Tabel

XIII

Killing dilutions

Solution ppm Quat + Chlorine- ppm Chlorine- ppm HEDTA- ppm Ammo-ppm-Chloridhex / HEDTA Total hexidine anion nium cation anion

ppm gluconate

ro ο co oo cn

A (control)

B.

C.

D.

E.

P.

G

Chlorhexidine

digluconate (control)

24
39
66
58
86
95

228

26th
44
71
65
94
105

675
405
173
124

47

18th

f 172

N3 Ki Ni

This table not only shows that mono- (chlorhexidine) -di (HEDTA) is a stronger bactericide compared to chlorhexidine digluconate, but that it is a synergistic one Effectiveness when mixing mono- (chlorhexidine ) -di (HEDTA) and didecyl-dimethyl-ammonium chloride leaves. From Fig. 1 it can be seen that with a simple additive effect of the two components, the test results should lie on line A, while in fact all observed values are on curve B, that is, far below A. lie. This means that the bactericidal properties of the mixtures are significantly greater than the sum of the individual components are, and that the mixtures therefore have a synergistic activity.

Example 30:

A 0.2 wt. # Solution of chlorhexidine di- (hydroxyethylethylenediamine triacetate) was obtained by dissolving 0.95 * 1 g Chlorhexidine base and 1.046 g of HEDTA in 1000 ml of distilled water and prepared with a 0.2 wt. ^ - igen solution of (Di-isobutyl-cresoxy-ethoxyethy ^ -dimethyl-benzyl-ammonium chloride (Trademark Hyamine 10X) mixed in distilled water in the following proportions:

Solution mono- (chlorhexidine) - "Hyamine 1OX" di- (HEDTA)

A 100 % 0%

B 75 % 25 %

C 50 % ■ 50 %

D 2H% 75 %

K (control) 0 % ' 100 %

209851/1236.

- 61 »-

In each case clear, stable solutions were obtained. Bacteriological studies

These solutions were made according to that described in Example 19 Method investigated; the results are shown in Table XIV and graphically in Figure 2 of the drawings.

20985 1/1236

Tabel

XIV

ro ο CD OO cn

CO

σ>

Total concentration
tration of
Bactericidal ppm Killing dilutions HEDTA
Anion
in ppm Quat cation
in ppm Chloride anion
in ppm solution 300 Chlorhexidine
Cation in ppm 157 0 0 A. 400 143 157 92 8th B. 500 143 - 131 230 20th C > 10Ö0 119 131 690 60 D. E (control) »1000 119 0 ^> 920 • »80 0

The results show that mono- (chlorhexidine) -di (HEDTA) is much more bactericidal acts as Hyamine 1OX, and that the mixtures of the Chlorhexid'inesälz and the Quat are synergistically effective, since curve B of the killing dilutions of the mixtures of the two compounds is substantially below the straight line A, which indicates which, additive effects of the two components would be expected (the experiments show that the killing Dilution of the quat is 2500 ppm, therefore line A is based on this).

VJI

ίο »

JOS.

N) N)

CD

Example 31:

. A according to Example 30 produced 0.2 wt # solution of chlorhexidine di (HEDTA) was treated with a 0.2 wt% solution of (di-isobuty l-phenoxy-äthoxyäthy].) - dimethyl-benzy 1-ammonium chloride mixed in distilled water in the following proportions:

solution Mono- (chlorhexidine) -
di- (HEDTA) "Hyamine 1622" 100 % A. 75 % 0 % B. 50 % 25 % C. 25 % 50 % D. E (control) 0 % 75 % 100 %

In each case clear, stable solutions were obtained. Bacteriological studies

The solutions A to E were, as described in Example 19, tested for their bactericidal activity. The results are shown in Table XV and graphically in Figure 3 of the accompanying drawings.

209851/1236

Table XV

Kill dilutions

solution Total concentration
of bactericides in ppm Chlorhexide
Cation in ppm HEDTA
Anion
in ppm Quat cation
in ppm Chloride-
Anion in ppm A. 250 119 131 O O ΙΌ
σ
CD
OO B.
η
T) 500
600
^> 1000 177
143
^ 119 p 198
157
> 131 115
276 ■ 10
24 E (control) )) 1000 O 0- ^> 920 »80

This table also shows that mono- (chlorhexidine) -di (HEDTA) is much stronger is bactericidal as the quat, and that the mixtures a.us the chlorhexidine salt and the Quat are synergistically effective because curve B of the killing dilutions of the mixture of the both components are below the straight line A, which would indicate the results that would be expected with a purely additive effect of the two components (results from the experiments found that the kill dilution of the quat alone is about 2500 ppm, so line A is refer to this basis).

Example 32:

A 0.2 wt. # Solution of Chlorhexidine-di- (HEDTA) was with a 0.2 wt. # - igen solution of cetylpyridium chloride mixed in the following proportions:

solution Mono- (chlorhexidine) -
di- (HEDTA) Cetylpyridinium
chloride A. 100 % 0 % B. 75 % 25 % C. 50 % 50 % D. 25 % 75 % E (control) 0 % 100 %

Here, too, clear, stable solutions were obtained in each case. Bacteriological studies

Solutions A to E were tested according to Example 19 for their bactericidal activity. The results are shown in Table XVI and graphically in Figure k of the accompanying drawings.

209851/1236

Table XVI

Solution Total concentration of the chlorhexidine bactericides in ppm cation in ppm

KEDTA anion
in ppm Quat cation
in ppm Chlond anion
in ppm I.
σ \
VO "el-
ίο
ο 157 0 0 157 90 10 157 270 30th 78 405 45 0 > 900 > .ioo

A 300 143

B 400 143

C 600 143

D 600. 72

E (control))> 1000 0

OD

In this case, too, it is clear that not only mono- ( chlorhexidine ) -di (KEDTA) is much more bactericidal than cetylpyridium chloride, but that the mixtures of the chlorhexidine salt and the quat Are synergistically effective, since the curve B of the killing dilutions of the mixtures lies below the straight line A, which would be expected with a purely additive effect of the two components (the experiments showed that the killing dilution [of cetylpyridium chloride is 2500 ppm, so that line A is related to this basis). P £

U) - CD

Example 33:

1.68 g of a 50% solution of coconut alkyl di (hydroxyethyl) benzyl ammonium chloride and 0.277 g of hydroxyethylethylenediamine triacetic acid were mixed with distilled water made up to 100 ml so that the molar ratio of quat cation to HEDTA anion in the solution was 2: 1 (solution I) A similar solution was then prepared which additionally contained 0.42 g of chlorhexidine (solution II). The two solutions were then mixed together in the following proportions:

solution Parts by weight
Solution I. Parts by weight
Solution II final solution
Weight? Chlorine weight %
hexidine ammon.
cation 0.769 Weight %
HEDTA
Anion A. 1 0 0 0.769 0.277 B. 5 1 0.07 0.769 0.277 C. 2 1 0.14 0.769 0.277 D. 1 1 0.21 0.769 0.277 E. 1 2 0.28 0.769 0.277 P. 0 1 0.42 0.277

Bacteriological examinations:

The solutions A to P were bactericidal according to Example 19 Activity investigated, with chlorhexidine-ddgluconate being tested as control compounds. The results are listed in Table XVII.

209851/1236

received

tab Hurry XVII ppm quat-
cation ppm HEDTA-
Anion ppm chlorine
hexidine
cation ppm
Gluconate Killing dilutions 551 199 G 0 solution Total-
bacteri
zide i.ppm 485 175 44 0 A. 750 343 123 62 0 B. 704 245 88 67 0 C. 528 221 79 80 0 D. 400 198 52 100 0 E. 380 F. 350 0 0 376 284 chlorine hexidine-66O digluconate

From the table it is clear that the mixtures with a Content of quat cations, HEDTA anions and chlorhexidine cations much better bactericidal effects than chlorhexidine digluconate and the quat sequestering agent salts.

Bei Piel 34:

Following the procedure described in Example 33, the following were made Solutions made:

Solution I Dioctyl-dimethyl-ammonium chloride -

209851/1236

o, '65 g.

HEDTA. 0.28 g

distilled water from 100 ml

Solution II

Dioctyl dimethyl ammonium chloride 0.64 g

HEDTA 0.28 g

Chlorhexidine 0.5 g

distilled water from 100 ml

These solutions were then mixed in the following proportions:

final solution

solution Parts by weight
Solution I. Parts by weight
Sol. II Wt% chlorine
hexidine Weight%
Ammonium-
cation Weight%
HEDTA
Anion A. 1 0 0 0.569 0.28 B. 7th 1 0.063 0.569 0.28 C. 3 1 0.125 0.569 0.28 D. 1 1 0.25 0.569 0.28 E. 1 2 0.33 0.569 0.28 F. 0 1 0.5 0.569 0.28

20985 1/1236

Bacteriological studies

The solutions A to P were tested according to the procedure described in Example 19 to their bactericidal activity _s using as control compound Chlorhexidine digluconate was used. The results are summarized in Table XVIII.

Tabel

XVIII

Killing dilutions

Solution ppm total
bactericidal 750 ppm quat-
cation ppm ■
HEDTA
Anion ppm-
Chlorine-
hexidine
cation ppm GIu-
conat-
Anion A. η 83 500 250 0 0 B. 516 300 150 33 0 C. 421 300 150 66 0 D. iJ23 217 108 96 0 E. .398 200 100 123 0 660 167 83 148 0 chlorine
hexidine
digluconate 0 0 376. 28M

209851/1236

The table shows that mixtures with a content larger in quatcations, HEDTA anions and chlorhexidine cations Effects as chlorhexidine digluconate and sequestering salts of the quat show.

Example 35

Mono (chlorhexidine) mono- (HEDTA) at 20 C only about 0.2% and mono- (chlorhexidine) di (HEDTA) is soluble in water at this temperature for only about 0.3%. This disadvantage can be compensated for by the fact that the solubility of the chlorhexidine salts is greatly increased by adding cetyl trimethyl ammonium bromide, so that a concentrate is formed.

Mixtures of chlorhexidine and HEDTA were dissolved in water and treated with cetyl trimethyl ammonium bromide, "Cetrimide", until a clear solution was obtained. These solutions can also be prepared by adding the solid chlorhexidine salt added to water and mixed with enough quat compound until a clear solution has formed.

In this way the following solutions were made:

209851/1236

■ -75 -

solution Weight %
Chlorine-
hexidine
cation' Weight %
HEDTA
anion Molver
ratio
Chlorhexi-
dine / HEDTA Weight # cetyl
trimethyl
ammonium-
bromide 20.7 A. Ik , 0 7.7 1: 1 20.0 1: 2 + 11.1
Excess B. 18.0 9.2 1: 1 + 17.6
Excess C. 7.2 7.1 1: 2 D. 5.5 8.3

All solutions prepared were clear and stable.

Bacteriological studies

Solutions A to D were tested for their bactericidal activity in the manner described in Example 19. With these Testing was done in Pseudomonas pyocyanea

A) hard standard water (W.H.0. regulation) without the addition of Serum,

B) distilled water with the addition of 10 % bovine serum and

C) hard standard water (WH0 regulation) with the addition of 10 % bovine serum

used. Chlorhexidine digluconate was also tested as a control compound. The results are summarized in Table XIX.

represents. ·

209851/1236

Table XIX: kill dilutions

A) Hard Standard water without serum 0 ppm
Cetrimide solution ppm chlorine
hexidine
cation 0 114 A. 80 ppm
HEDTA- ppm
anion gluconate 0 289 B. 200 45 0 288 C. 100 100 162 D. 80 100 120

Chlorhexidine digluconate 570

430

B) Distilled water + 10 % serum

solution ppm chlorine
hexidine
cation ppm
HEDTA
anion ppm
Gluconate ppm
Cetrimide A. 130 70 0 185 B. 100 50 0 145 C. 50 • 50 0 144 D. 60 90 0 121 " Chlorhexidine
digluconate 285 0 215 0

209851/1238

C) Standard hard water + 10% serum

solution ppm chlorine
hexidine
cation ppm
HEDTA
anion ppm
Gluconate ppm
Cetrimide A. 320 l80 0 H56 B. 760 390 0 1097 C. 390 380 0 1124 D. 200 300 0 405 Chlorhexidine
digluconate 11 * 15 0 855 0

From these experiments it is found that by adding cetyltrimethylammonium bromide and an aminocarboxylic acid effective as a sequestering agent for solutions containing chlorhexidine, the addition of chlorhexidine necessary to achieve a certain bactericidal effect is significantly reduced can be. Since HEDTA and Cetrimide are significantly cheaper than Chlorhexidines, this leads to a sharp decrease the cost of producing disinfectants and, on the other hand, the effectiveness of a disinfectant without Consideration of the costs can be increased significantly "

Example 36

According to the method described in Example 35, the following mixtures of chlorhexidine-DTPA and cetrimide were produced

209851/1236

which resulted in clear, stable solutions:

Weight? Chlorhexidine- wt.% . Weight? Solution cation DTPA-anion Cetrimide

A 10.5 7.5 15.0

B 13, ¹ I 6.5 19.5

Bacteriological studies The solutions were bactericidal as in Example 35 Activity checked in A) hard standard water (W.H.0. regulation) without serum, B) distilled water + 10 % bovine serum and C) hard standard water (WH0 regulation) + 10 % bovine serum.

Chlorhexidine digluconate was tested with off as a control compound. The results are shown in Table 20.

Table XI; Ötungsverdünnungen from I

A) Hard Standard water without serum 0
0 ppm
Cetrimide solution ppm chlorine
hexidine
kat ■ »on 86
98 A 60
B 67
Chlorhexidine ppm
DTPA- ppm
anion gluconate HO
33

digluconate 570 0 430 0

209851/1236

B) Distilled water + 10 % serum

ppm chlorine- ppm

hexidine- DTPA- ppm

Solution cation anion gluconate

A 90 60 0

B 100 50 0

Chlorhexidine

digluconate 285 O 215

ppm cetrimide

129

C) Standard hard water + 10 % serum

solution ppm chlorine
hexidine
cation ppm
DTPA
anion ppm
Gluconate ppm
Cetrimide A. 300 200 0 430 B. 670 330 0 980 Chlorhexidine
digluconate 1145 0 855 0

Here, too, it is shown that the effectiveness of bactericidal mixtures containing chlorhexidines is achieved by adding cetrimide and DTPA can be improved with a corresponding reduction in costs.

Similar results are obtained with mixtures of chlorhexidines, Obtained NTA as a sequestering agent and cetrimide.

209851/1236

Example 37

The compounds of the invention are not only against
Pseudomonas pyocyanea effective, but also against numerous
other bacteria. Solution A) from Example 35 and solution A) from Example 36 were with chlorhexidine digluconate as a control compound with regard to their bactericidal effectiveness against
numerous other bacteria tested. The tests were carried out as described in Example 19, with distilled
Water with an addition of 10 % bovine serum was used. The following germs were used as test germs:

1) Pseudomonas pyocyanea N.C.T.C. 67 ^ 9

2) Proteus vulgaris N.C.T.C. H635

3) Salmonella typhi N.C.T.C. 3390 1 ») Escherichia coli N.C.T.C. 8196

5) Staphylococcus aureus N.C.T.C. 3750

The results of these experiments are summarized in Table XXI.

209851/123 &

Table XXI: kill dilution

Chlorhexidine salt

Ps.

solution

l) pyo. 2) P.vulg. 3) S.typhi

5) Staph.aur.

Example 35
Solution A) 200

Example 36
Solution A) 150

Chlorhexidine digluconate 500

300 350 750

100

100

300

150 200 300

200

100

500

These results also show that the mixtures according to the invention are much stronger than chlorhexidine digluconate are effective against numerous bacteria.

Example 38

The results obtained in the above example against E. coli were further confirmed by the bactericidal properties of the mixtures against E. coli according to the methods already described in British Standard 3286: 1960 in hard standard water (WH0. Regulation) with a content of 10 % Bovine serum were performed. The following solutions were used, chlorhexidine digluconate being used as the control compound:

2 0 9 8 51/12 3 8

Wt.% Chlorine
Solution of hexidine cation 13.0 Weight %
HEDTA anion Weight /?
DTPA anion Weight %
NTA anion Weight %
Gluconate anion Cetrimide A. 13.6 7.2 0 0 0 18.9 B. 14.4 0 6.5 0 0 11.3 C. 11.4 0 0 5.1 0 15.4 Chlorhexidine
digluconate
(Control) 0 0 0 8.6 0

O CO CO cn

~ * These mixtures have been tested in concentrations equal to 100, 150, 200, 250, 300,

^ 350, 400, 500, 600, and 800 ppm of the inventive Chlorhexidine salts or chlorine cn hexidine digluconate correspond. The results of the tests are expressed in Table XXII as the number of germs surviving per million bacteria inoculated.

OO

NJ

CD

Test 1 A.
test 2 test 3 Test 1 Tabel _ test C.
1 test 2 test 3 Chlorhexidine
digluconate (Ko
Test 1 Test 2 ntroll
Test 3 ppm chlorine
hexidine /
Sequestrans
salt _ i XXII 85 u / c _ 100 - - 137 -. solution
B.
Test 2 Test 3 30th 432 36 u / c - - 1.50 190 78 27 260 _ - O - O - - 200 0 - - - 24 O O - O - - 250 0 0 O 113 O O O 44 O u / c - 300 0 0 O O - O O O .0 133 • 162 400 0 O O O O O O O O 174 '- 110 . 500 0 0 O O O O O O O 100 0 23 600 0 0 O O O O O O 0 0 0 800 O O

The table clearly shows that these mixtures are much more bactericidal against E.coli are effective as chlorhexidine * digluconate.

N) N> CJ

Claims (31)

Claims 1.1 Salts from bactericidally active bis-biguanide bases with as Aminocarboxylic acids with sequestering agents. 2. Salts according to claim 1, characterized in that the Bactericidally active bis-biguanide bases of the general formula I A-NH-C-NH-C-NH-X-NH-C-NH-C-NH-A (I) IJ J Il NH NH NH NH correspond, in which A identical substituted or unsubstituted phenyl or phenylalkyl groups, in which the alkyl group has 1 to 3 carbon atoms and in which each "phenyl group with one or more halogen atoms or hydroxy, nitro, alkyl, alkoxy or Alkylthio groups can be substituted, and in which X either a bridge member such as a benzene, dialkoxybenzene or cyclohexane ring or a polymethylene chain with 1 to 15 -CH ₂ "groups, which can optionally be interrupted by one or more oxygen atoms and / or optionally by one or several benzene rings or diphenylmethylene groups can be interrupted or terminally substituted, or in which X is the group NH-X-NH (where X has the above meaning 209851/1236 with terminal imino groups} which leads to a piperazinyl. ring is closed, mean. 3. Salts according to claim 2, characterized in that the bisbiguanide base ' 1,2-bis (N.-p-chloropheny ldiguanido-Nj.) Ethane; to / o'-bis (N.-p-chloropheny ldiguanido-N, -) - di-n-propyl ether; 1,6-bis (N.-ß-phenylethyldiguanido-Nc) -hexane; 1,6-bis- (N-phenyldiguanido-Nci-hexane; 1,6-BiS- (N. -2, M-dimethylphenyl diguanido-N, -) -hexane; 1 5 1,6-bis (N -p-tolyldiguanido-N,.) - hexane; 1,6-bis- (N., -p-hydroxyphenyldiguanido-N, -) -hexane: 1,6-bis- (N ₁ -p-anisyldiguanido-N ₍ -) -hexane; 1,6-bis- (N.-m-nitrophenyldiguanido-N, -) -hexane; 1,3 ~ bis- (N ^ -p.-chlorpheny ldiguanido-Nc) propane; l, i | bis- (N ₁ -p-chlorophenyldiguanido-N _t -) - butane; l, 5-bis- (N ₁ -p-chlorophenyldiguanido-N _t -) - pentane; l, 7 ~ bis- (N.-p-chlorophenyldiguanido-Np.) - heptane; 1,6-bis- (N. -m-chloropheny ldiguanido-N, -) -hexane; 1, 6-bis- (N.-2,5-dichlorophenyldiguanido-Nc) -hexane; 1,6-bis- (N.-3 j ^ -dichlorophenyldiguanido-Nc) -hexane; 1, ¹ I-BiS- (N. -pheny ldiguanido-N, -) -benzene; 1, Jl-BiS- (SL -p-chlorpheny ldiguanido-N-) -benaol; 1 0 ' 1,6-bis (N.-p-chlorophenyl diguanido-N, -) -hexane; 1 0 20 9851/1236 l, 10-bis (N -p-chlorophenyldiguanido-lO-decane: 1, ¹ I-bis- (N -o-chlorophenyldiguanido-N ,.) hexane;.. 1 t) 4,4'-bis (N ₁ -phenyl diguanido-Nj -) - diphenyl methane; 4,4'-bis- (N ₁ -p-chlorophenyldiguanido-N _l _) - diphenylmethane; , Cu * -Bis- (N.-p-chlorophenyldiguanido-Nj.) - 1,4-di-n-propoxybenzene or
1,4-BiS- (N.-p-chlorophenylamidinoamino-Nju) -piperazine is present. 4. Salts according to claim 1 to 3, characterized in that the aminocarboxylic acid effective as a sequestering agent has the general formula II HOOC CH ₂ N (R ¹ ) ZR ² , in which R is a hydrogen atom, an alkyl, carboxymethyl, hydroxy 2 ethyl or hydroxypropyl group, R a carboxymethyl, Hydroxyethyl or hydroxypropyl group and Z either the group -CH _{3 .CH 2} -N (R ^) _n -, in which R ^{5 has} the meaning of R ¹ and η can be 0, 1, 2 or 3, or in the Z group III N (R ³ ) - _v (III) in which R has the meaning given, mean. 209851/1 236 received *8th 5. Salts according to claim 1 to 4, characterized in that present as aminocarboxylic acid: Ethylenediamine tetraacetic acid; N, N ¹ -ethylene diamine diacetic acid; N-hydroxyethyl-ethylenediamine-triacetic acid; N, N ', - Dihydroxyäthy 1-äthy lenediamine-diacetic acid; Diethylenetriamine pentaacetic acid; 1,2-diaminocyclohexane tetraacetic acid; Nitrilotriacetic acid; N-hydroxyethyl irainodiacetic acid; . N-Dihydroxyäthyl-aminoesBigsäure iminodiacetic acid, or 3-hydroxypropyl iminodiacetic acid. 6. Mono-chlorhexidine- (ethylenediamine tetraacetate). 7. Mono-chlorhexidine (nitrilotriacetate). 8. Mono-chlorhexidine (diethylenetriamine pentaacetate). 9 »Mono-chlorhexidine- (N-dihydroxyethyl-aminoacetate). 10. Mono-picloxidine-ethylenediamine-tetraacetate). 209851/1236 -θ9 - 11. Mono-picloxidine-cnitrilotriacetate). 12. Mono-picloxidihe- (N-dihydroxyethyl-aminoacetate). 13. Mono-picloxidine (diethylenetriamine pentaacetate). 14. Mono-jj., 6-bis- (N-p-methylthiophenyldiguanido-N-) -hexane- (N-hydroxyethy1-ethylenediamine triacetate). 15 · Mono-chlorhexidine-iN-hydroxyethyl-ethylenediamine-triacetate). 16. Mono-chlorhexidine di-J_N-hydroxyäthyl-ethylenediamine triacetate. 17 · Process for the preparation of the salts according to Claims 1 to 16, characterized in that the bis-biguanide base in one aqueous or aqueous-alcoholic medium is reacted with the aminocarboxylic acid. 18. Process for the preparation of the salts according to claim 1 to 16, characterized in that a salt of the bis-biguanide base with a salt of the aminocarboxylic acid in an aqueous or aqueous-alcoholic medium in a double reaction is implemented. 209851/1236 - gtj - " 19 · The method according to claim 17 or 1.8, characterized in that that aqueous methanol and / or ethanol is used as the aqueous-alcoholic medium. 20. Disinfectants or antiseptics containing Compounds according to claim 1 to 16 in a suitable '. solid or liquid carrier. 21. Disinfectants or antiseptics according to claim 20, da-. characterized by the fact that they are a solution yermittler contain quaternary ammonium compound. 22. Disinfectants or antiseptics according to claim 21, characterized in that they are a quaternary ammonium compound of the general formula IV -f- (IV) Y ¹ - 4 - Y ² CH ₃ contain, in which Y is an alkyl group with 8 to 20 carbon atoms, a di-isobutyl-phenoxy-ethoxyethyl or a di-isobutyl cresoxy-ethoxyethyl group, Y an aralkyl group optionally substituted in the aromatic nucleus and preferably mean a Benzy! group. 209851/1236 23. Disinfectants or antiseptics according to claim 22, characterized in that they are a salt of benzalkonium, des (di-isobutyl-cresoxy-ethoxyethyl) -dimethyl-benzyl-ammonium, des (di-isobutyl-phenoxy-ethoxyethyl) -dimethyl-benzyl-ammonium or of myristyl-dimethyl-benzyl-ammonium. 24. Disinfectants or antiseptics according to claim 20, characterized in that it is a quaternary ammonium compound of the general formula V CH. Y ^ -N-CH CH. contain, in which Y is either an alkyl group with 8 to 18 carbon atoms or an alkylbenzyl group in which the alkyl group has 8 to 18 carbon atoms. 25 · Disinfectants or antiseptics according to claim 2k, characterized in that they contain cetyl trimethyl ammonium bromide. 26. Disinfectants or antiseptics according to claim 20, characterized in that they are a quaternary ammonium compound of the general formula VI 209 851/1236 received on CH. Υ ^η - N - CH. (VI) contain, in which Y and Y ⁵ each represent an alkyl group with 8 to 18 carbon atoms and can be identical or different. 27. Disinfectants or antiseptics according to claim 26 _9, characterized in that they contain salts of didecyl-dimethylammonium or of dioctyl-dimethylammonium. 28. Disinfectants or antiseptics according to claim 20, characterized characterized in that they contain quaternary ammonium compounds of the general formula VII Y '- N - CH (VII) contain, in which Y is an alkyl group with 8 to 20 carbon atoms 7 R
and Y and Y are identical or different hydroxyalkyl or alkoxyalkyl groups. 29. Disinfectants or antiseptics according to claim 28, characterized in that they are salts of alkyl-dihydroxyethyl-benzyliammonium contain" 20 9 8517 12 30. Disinfectants or antiseptics according to claim 20, characterized characterized in that they contain quaternary ammonium compounds of the general formula VIII. (VIII) contain, in the Y ^ an alkyl group with 8 to 20 carbon atoms means. 31. Disinfectants and antiseptics according to claim 30, characterized characterized in that they contain cetylpyridinium bromide. si: kö 209851/1236 Blank page