DE2633651A1 - BIS BIGUANIDO COMPOUNDS AND ORAL AND / OR DENTAL CARE PRODUCTS CONTAINING THE SAME - Google Patents

Description

LAWYERS -

DR. JUR. DIPL-CHEM. WALTER BEIL ^ JULY 6, 1976

ALFRED HOEPPENER

DR. JUR. DIPL-CHEM. H.-J. WOLFF

DR. JUR. HANS CHR. AX

623 FRANKFURTAM MAIN-HOCHS?

AD £ lOKSTRAäS £ 5B

Our No. 20 6l4

The Procter & Gamble Company Cincinnati, Ohio, V.St.A.

Bis-biguanido compounds and oral and / or dental care products containing the same

The invention relates to new bis-biguanido compounds and the same Containing oral and / or dental care products, i.e. products to be used orally which, in their normal use during a certain Remain in the oral cavity for time and in such a way that it touches virtually all tooth surfaces, but not on purpose be taken. Such agents are, for example, dentifrices, Mouthwashes, prophylactic pastes and solutions for topical use (topical solutions). The new bis-biguanido compounds inhibit the formation or development of plaque and caries.

It is known that the anti-bacterial bis-biguanide, such as Chlorhexidine, 1,6-bis (N -p-chlorophenyl-N-biguanido) -hexane, as Antiplaque agents are suitable, but can cause pronounced staining of the teeth. In BE-PS -801 703 is the use insoluble salts of bis-biguanides in oral and / or dental care products to reduce the problem of staining teeth suggested. In BE-PS 8II 87S and the German patent application P 25 34 887.2 -70 980 77 1159

describes the use of metal ion chelating agents such as amino acids, aminopolycarboxylates and hydroxypyrones along with the bis-biguanides to reduce tooth staining. In the German application P 26 27 5 ^ 8.9 certain bis-biguanides are described whose alkylene bridges contain 1 to U carbon atoms instead of 6 carbon atoms, and which have a significantly lower tendency to stain than chlorhexidine,

It has been found that certain new bis-biguanide compounds, whose alkylene bridging group contains 1 to 4 carbon atoms and whose terminal nitrogen atoms carry trifluoromethylphenyl groups, an excellent anti-plaque effect and a very low one Have a tendency to stain teeth.

The new bis-biguanide compounds according to the invention have the general formula

R NH NH R ₂ R ₂ ¹ NH NH R '(X) -NC-NH-C - N- (CH-) -N - C-NH-C - N-

Z Δ Ti

in which η is a number from 1 to 4 inclusive, preferably 2 to 4 inclusive, X and X ^f each represent an alkylene radical containing 1 to 3 carbon atoms, ζ and z ^{T are} each either zero or one, R and R ¹ each represent either hydrogen atoms, ₉ alkyl radicals with 1 to about 12 carbon atoms or aralkyl radicals with 7 to about 12 carbon atoms, and R "and R 'are each hydrogen atoms or alkyl radicals with 1 to 2 carbon atoms.

Preferred is the compound in which ζ and z ¹ each

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Are zero, η is two and R, R ¹ , R and R 'are hydrogen atoms. The trifluoromethyl group is preferably in the meta position, but the corresponding ortho and para isomers are also suitable here.

The pharmacologically acceptable or pharmaceutically acceptable ones Salts of the above compounds are particularly useful. The water-soluble salts, especially the dihydrochloride digluconate and diacetate salts, are particularly advantageous because they enable the formation of compositions as clear solutions enable. In contrast to chlorhexidine, the dihydrochloride of which is insoluble in water, the hydrochlorides are

water-soluble of compounds according to the invention. The hydroder

The chloride salt is typically formed from the production of chlorhexidine and of compounds according to the invention inevitably.

In the present context, salts are considered water-soluble if they are in 1
as about 0.04 wt%.

lent, if they had a solubility of more than 25 C in water

Examples of bis-biguanides according to the definition according to the invention are the following

Bis (N -m-trifluoromethylphenyl-N-biguanido) methane 1,2-bis (N -m-trifluoromethylphenyl-N-biguanido) -ethane, 1,4-bis (N -m-trifluoromethylphenyl-N-biguanido) -butane, l, 2-bis (N -m-trifluoromethylbenzyl-N-biguanido) ethane, 1,2-bis (N -p-trifluoromethylphenyl-N-biguanido) -ethane, l, 2-bis (N -o-trifluoromethylphenyl-N-biguanido) -ethane,

1, .2-bis (N -m-trifluoromethylphenyl-N -hexyl-N-biguanido) ethane,

1,2-bis (N -m-trifluoromethylphenyl-N -2-phenethyl-N-biguanido) ethane,

1,2-bis (N ⁵ -m-trifluoromethylphenyl-N ¹ -ethyl-N ¹ -biguanido) -ethane, 1,4-bis (N ⁵ -m-trifluoromethylphenyl-N ⁵ -ethyl-N ¹ -methyl-N ¹ -

1,2-bis (N ⁵ -m-trifluoromethyl-N ⁵ -methyl-N ¹ -ethyl-N ¹ -biguanido) -

biguanido) -butane,

• m-trif:
ethane,

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as well as the water-soluble salts of these compounds, e.g., the digluconate, dihydrochloride and diacetate salts. 1,2-bis (N m -trifluoromethylphenyl-N -biguanido) ethane and the dihydrochloride, diacetate or digluconate salts thereof are on most preferred.

The compounds according to the invention can be prepared by ^{reacting the ethylene or methylenediamine dihydrochloride (or a correspondingly N, N 1} -substituted ethylene or methylenediamine hydrochloride) with sodium dicyanamide, for example a bis (N -cyano-N -guanicSo) -ethane to form, which is then reacted with the hydrochloride of the desired m-trifluoromethylphenylamine to give the desired bis-biguanide compound in the form of its hydrochloride salt. This general production method for bis-biguanides is known as such, see, for example, Warner et al, J. Pharm. Sci. 6> _2 No. 7, 1189-91 (1973) and Rose et al, J. Chem. Soc. 4422 (1956).

The new bis-biguanide anti-plaque active ingredients according to the invention are used for oral hygiene in the form of oral and / or dental care products ("oral preparations") which - bescgen by weight - about 0.01% to about 2.5% (preferably about 0.05% to about 1.2%, and more preferably about 0.1% to about 0.8%) bis-biguanide antiplaque active ingredient and the remaining part a carrier suitable for use in the oral cavity contain. Unless otherwise stated, all percentages given below are based on weight. Depending on the composition or the type of agent, smaller or larger proportions can also be used. In general all that is required is that there be an effective amount of bis-biguanide compound in the mouth, which is sufficient for the anti-plaque and / or anti-caries effectiveness. Generally, amounts of 0.001 g or more of bis-biguanide will be used per application as effective plaque control amounts viewed.

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The pH value of the agents according to the invention is preferably im Held in the range from about 4.5 to about 9.5. At values below about 4.5, the enamel can be damaged. Values of Above 9.5 creates a cosmetically undesirable alkalinity and can irritate the soft tissues of the mouth.

As mentioned above, included

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the means according to the invention are those described above Bis-biguanide anti-plaque agents and one for use suitable carrier in the oral cavity. The carrier can be water or an organic solvent such as alcohol. Preferably if the carrier component of the oral and / or dental care product is a common toothpaste, mouthwash preparation, Chewing gum paste or the like.

Dental care products or dentifrices contain an abrasive or abrasive polishing agent and usually also a foaming agent, Flavor and sweetener. Toothpastes also usually contain humectants, binders and water. Dental care products or dentifrices according to the invention can additionally contain about 0.5% to about 95% abrasives or abrasives to the bis-biguanide antiplaque active ingredient.

For such dentifrices, all abrasive or abrasive polishing agents can be used that the dentin does not Abrasive excessively. These include, for example, calcium carbonate, dicalcium orthophosphate dihydrate, calcium pyrophosphate, Calcium polymetaphosphate and insoluble sodium polymetaphosphate. Preferably, abrasives or abrasives are used which are highly compatible with the bis-biguanide. These include For example, condensation products of urea and formaldehyde, as described in US Pat. No. 3,070,510, silica xerogels, as described in US Pat. No. 3,538,230, with Hydrofluoric acid treated amorphous silicas, such as those described in US Pat. No. 3,862,307, and mineral ones Abrasives or abrasives coated with cationic polymers, as described in DT-OS 2 522 046. described is. The particle sizes or particle diameters of the abrasives or abrasives are mostly between about 0.1 and about 20 Micron.

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The total proportion of abrasive or scouring agents in the preparations according to the invention suitable as dentifrices can be approximately 0.5 to 95% of the weight of the dentifrice. In the case of toothpastes, the amount of abrasive or scouring agent is preferably about 6 to about 60%, with tooth powder about 20 to about 95%.

Dental care products or dentifrices usually also contain surface-active agents Agents or surfactants (also known as foaming agents).

Suitable surfactants should be relatively stable, have a foam-forming effect in a broad pH range and not with the bisbiguanide compound react. It can be non-soap / non-ionic, cationic, zwitterionic and amphoteric organic synthetic surfactants or detergents are used.

Suitable for oral and / or dental care products according to the invention nonionic synthetic detergents can be broadly defined as compounds formed by condensation of alkylene oxide groups (hydrophilic behavior) with organic hydrophobic compounds that are aliphatic or alkyl aromatic Connection can be available. The length of the hydrophilic group condensed with a given hydrophobic group, d. H. of the polyoxyalkylene radical, can be selected without difficulty so that a water-soluble compound with the desired A balance of properties between the hydrophilic and hydrophobic components is created.

For example, a well-known group of non-ionic is synthetic Detergents are commercially available under the trade name "Pluronic". These compounds are made by condensing made of ethylene oxide with a hydrophobic base, generated by the condensation of propylene oxide with propylene glycol

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forms is. The hydrophobic and naturally water-insoluble part of the molecule has a molecular weight of about 1500 to around 1800. The addition of polyoxyethylene groups to this hydrophobic part works towards increased water solubility of the total molecule and the liquid character of the products is retained until the polyoxyethylene content is about 50% of the The total weight of the condensate.

Other suitable non-ionic synthetic detergents include:

1. Polyethylene oxide condensates of alkyl phenols, e.g. B. the condensates from alkylphenols that contain an alkyl group with about 6 to 12 carbon atoms in a straight or twisted chain, and ethylene oxide in proportions of 10 to 60 moles of ethylene oxide per mole of alky! phenol. The alkyl substituent of such compounds can e.g. B. derived from polymerized propylene, diisobutylene, octane or nonane.

2. Products of the condensation of ethylene oxide with the products of the reaction of propylene oxide and ethylene diamine, d. H. Substances whose composition depends on the desired property balance of the hydrophobic and hydrophilic components can be changed. For example, compounds of about 40 to about 80% by weight of polyoxyethylene are suitable, which have a molecular weight of about 5000 to about 11,000 and by reacting the ethylene oxide groups with a hydrophobic base is formed, which is the product of the reaction of ethylenediamine with excess propylene oxide and a molecular weight on the order of 2500 to 3000 owns.

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3. The condensation product of aliphatic alcohols containing 8 to 18 carbon atoms in a straight or branched chain, with ethylene oxide, e.g. B. a coconut alcohol / ethylene oxide condensate, which contains 10 to 30 moles of ethylene oxide per mole of coconut alcohol, the coconut alcohol fraction Contains 10 to 14 carbon atoms.

4. Long chain tertiary amine oxides of the formula

R ₃ R ₄ R ₅ N > O

in which R is an alkyl, alkenyl or monohydroxyalkyl radical from about 8 to about 18 carbon atoms with zero to about ten ethylene oxide groups and zero to 1 glyceryl groups and R. and R each contain 1 to about 3 carbon atoms and zero to about 1 hydroxyl groups, e.g. B. methyl, ethyl, propyl, Hydroxyethyl or hydroxypropyl radicals. The arrow in the formula is the usual representation of a semi-polar bond. Examples of amine oxides suitable for use in the invention include: dimethyldodecylamine oxide, Oleyldi (2-hydroxyethyl) amine oxide, dimethyloctylamine oxide, Dimethyldecylamine oxide, dimethyltetradecylamine oxide, 3,6,9-trioxaheptadecyl diethylamine oxide, di (2-hydroxyethyl) tetradecylamine oxide, 2-dodecoxyethyldimethylamine oxide, 3-dodecoxy-2-hydroxypropyl-di (3-hydroxypropyl) -amine oxide, Dimethylhexadecylamine oxide.

5. Long chain tertiary phosphine oxides of the formula

in which R _{r is} an alkyl, alkenyl or monohydroxyalkyl radical with 8 to 18 carbon atoms chain length, zero to about 10 ethylene oxide groups and zero to 1 glyceryl groups and R ₇ and R _{0 are} each alkyl or monohydroxyalkyl groups,

⁸ 7 09 807/1159

which contain 1 to 3 carbon atoms. The arrow again means a semi-polar bond. Examples of suitable phosphine oxides are among others: dodecyldimethylphosphine oxide, tetradecyldimethylphosphine oxide, Tetradecylmethylethylphosphine oxide, 3,6,9-trioxaoctadecyldimethylphosphine oxide, cetyldimethylphosphine oxide, 3-dodecoxy-2-hydroxypropyl-di (2-hydroxyethyl) -phosphine oxide, Stearyldimethylphosphine oxide, cetylethylpropylphosphine oxide, oleyldiethylphosphine oxide, dodecyldiethylphosphine oxide, Tetradecyl diethyl phosphine oxide, dodecyl dipropyl phosphine oxide, dodecyl di (hydroxymethyl) phosphine oxide, Dodecyl-di (2-hydroxyethyl) -phosphine oxide, tetradecylmethyl-2-hydroxypropyl-phosphine oxide, Oleyl dimethyl phosphine oxide, 2-hydroxydodecyl dimethyl phosphine oxide.

6. Long-chain dialkyl sulfoxides, which contain a short-chain alkyl or hydroxyalkyl radical with 1 to about 3 carbon atoms (mostly methyl) and a long hydrophobic chain that contain a Alkyl, alkenyl, hydroxyalkyl or ketoalkyl radical with about 8 to about 20 carbon atoms, zero to about 10 ethylene oxide groups and zero to 1 are glyceryl groups. Examples of such compounds include: Octadecyl methyl sulfoxide, 2-ketotridecylmethyl sulfoxide, 3,6,9-trioxaoctadeyl-2-hydroxyethyl sulfoxide, Dodecyl methyl sulfoxide, oleyl 3-hydroxypropyl sulfoxide, Tetradecyl methyl sulfoxide, 3-methoxytridecyl methyl sulfoxide, 3-hydroxytridecylmethyl sulfoxide, 3-hydroxy-4-dodecoxybutylmethyl sulfoxide.

Suitable for oral and / or dental care products according to the invention Zwitterionic synthetic detergents can generally be used as derivatives of aliphatic quaternary ammonium, phosphonium and Sulfonium compounds are described whose aliphatic radicals have straight or branched chains, one of the aliphatic groups containing about 8 to 18 carbon atoms and another an anionic, water-solubilizing group, e.g. B. a carboxy, sulfonate, sulfate, phosphate or phosphonate

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group. These compounds can correspond to the following formula :

I / ι \

R _g - Y ^v;

in which R is an alkyl, alkenyl or hydroxyalkyl radical with about 8 to about 18 carbon atoms, zero to about 10 ethylene oxide groups and zero to 1 glyceryl groups, Y is the nitrogen, phosphorus or sulfur atom, R, _{Q is} an alkyl or monohydroxyalkyl group with 1 to about 3 carbon atoms and χ is equal to one when Y is the sulfur atom, and is equal to two when Y is a nitrogen or phosphorus atom, R _{11 is} an alkylene or hydroxyalkylene group with 1 to about 4 C- Atoms and Z is a carboxylate, sulfonate, sulfate, phosphonate or phosphate group. Specific examples include the following:

4- [N, N-di (2-hydroxyethyl) -N-octadecylammonium I-butane-1-carboxylate, 5- [s-3-hydroxypropyl-S-hexadecylsulfonium] -3-hydroxypentane-1-sulfate, 3- [p, P-diethyl-P-3,6,9-trioxatetradecoxy! Phosphorus ?! -2-hydroxypropane-l-phosphate, 3-iNjN-dipropyl-N-S-dodecoxy-2-hydroxypropylammoniumJ-propane-l-phosphonate, 3- (N, N-dimethyl-N-hexadecylammonium) -propane-1-sulfonate, 3- (Ν, Ν-dimethyl-N-hexadecylammonium) -2-hydroxypropane-l-sulfonate, 4- | N, N-di (2-hydroxyethyl) -N (2-hydroxydodecyl) ammonium j-butane-1-carboxylate, 3- [S-ethyl-S (3-dodecoxy-2-hydroxypropyl) -sulfoniumj -propane-1-phosphate, 3- [ρ, Ρ-dimethyl-P-dodecylphosphonium / propane-1-phosphonate and 5- [N, N-di (3-hydroxypropyl) -N-hexadecylammonium I -2-hydroxypentane-1-sulfate.

Cationic synthetic detergents suitable for oral and / or dental care products according to the invention can generally be used as quaternary Ammonium compounds are described with a long alkyl chain which contains about 8 to about 18 carbon atoms, such as

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Lauryltrimethylammonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, Di-isobutylphenoxyethyldimethylbenzylammonium chloride, Coconut alkyltrimethylammonium nitrite, cetylpyridinium fluoride, etc. Particularly preferred are the quaternary ammonium fluorides described in US Pat. No. 3,535,421 Detergent properties.

Amphoteric synthetic detergents suitable for the invention can generally be used as derivatives of aliphatic, secondary and tertiary amines in which the aromatic radical has a straight or branched chain and in which one of the aliphatic substituents has about 8 to about 18 carbon atoms and one is anionic, water-soluble making group contains, e.g. B. the carboxylate, sulfonate, sulfate, Phosphate or phosphonate group. Examples according to this definition are: sodium 3-dodecylaminopropionate, sodium 3-dodecylaminopropanesulfonate, Dodecyl-beta-alanine, N ^ -alkyltaurine, such as are obtainable by reacting dodecylamine with sodium isethionate according to US Pat. No. 2,658,072, N-higher alkylaspartic acids, as are available according to US Pat. No. 2,438,091, as well as those available under the trade name "iliranol" and products described in U.S. Patent 2,528,378.

Numerous other nonionic, cationic, zwitterionic and amphoteric synthetic detergents are known and can in agents or preparations according to the invention as foaming agents be used. Further examples are in "McCutcheon's Detergents and Emulsifiers, 1972 Annual "published by Allure Publishing Corporation.

The foaming agent can be used in proportions of about 0.5 to about 5.0% of the dentifrice or dentifrice can be used.

Dentifrices and dentifrices usually also contain flavorings. Examples of suitable flavors for

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Use for the present dental care or dentifrice include winter green oil (methyl salicylate), Peppermint oil, sassafras oil (synthetic) and anisole. Taste substances are mostly used in proportions of 0.01 to 2.0%.

Dentifrices or dentifrices usually also contain sweeteners or sweeteners. For dentifrices are below other saccharin, dextrose and levulose are suitable. The sweeteners are usually used in proportions of about 0.05 to about 2% used.

Toothpastes expediently also contain thickeners such as hydroxyethyl cellulose and water-soluble salts of cellulose ethers including sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose, natural gums or plant mucilages such as karaya gum, ommi arabicuin , tragacanth. Colloidal ilagnesium aluminum silicate or finely divided silicon dioxide can also be used as part of the thickening agent to improve the texture of the product. Thickeners are mostly used in proportions of 0.1 to 5.0% of the toothpaste preparation.

Toothpastes also conveniently contain humectants. Suitable substances include glycerine, sorbitol and others ingestible polyhydric alcohols or mixtures thereof. Such substances can make up about 1 to about 50% of the toothpaste preparation turn off. Except for the typical toothpaste components mentioned above there is usually water as the remainder, generally up to about 50%.

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Mouthwashes usually contain a water / ethyl alcohol solution and optionally further components such as flavors _r sweeteners and humectants the above in connection with dentifrices mentioned type. The alcohol content allows an antibacterial effect. Mouthwashes can also contain foaming agents, as mentioned above in connection with dentifrices. Humectants, such as glycerine and sorbitol, give the mouth a moist feeling and are expediently also used here. Mouthwashes or dentifrices sometimes also contain antibacterial substances in proportions of about 0.01 to about 2.0%.

Mouthwashes, which are suitable for use as carriers here, contain 5 to 40% ethyl alcohol, zero to 20% (preferably 5 to 20%) glycerin or other humectant, zero to 2% (preferably 0.1 to 2%) foaming agent, zero up to 0.5% (preferably 0.05 to 0.5%) sweeteners, such as saccharin, Zero to 0.3% (preferably 0.05 to 0.3%) flavor and the remainder water.

Chewing gums, which are suitable for use as carriers here, contain chewing gum base and flavorings of the type mentioned above in connection with dentifrices. The flavoring component usually corresponds to 0.01 to about 2.0% of the finished chewing gum preparation. The gum base is a chewable plastic gum material, _r - z. B. made of natural rubber, chicle, polyvinyl acetate, ester rubber, coumarone resin and paraffin resin. Typical chewing gum bases usually contain mixtures of two or more gum components in order to achieve the degree of plasticity desired for chewability. If desired, chewing gum can also contain corn syrup as a plasticizer and binding agent and sugar as a filler or sweetener. A typical chewing gum useful as a carrier herein contains 15 to 30% chewing gum base, 15 to 20% corn syrup, 50 to 65% sugar and 0.05 to 1.5% flavoring agents.

709807/1159

Oral lozenge preparations, as they are often called mostly diamond-shaped Lozenges are used and are suitable here as a carrier, contain a hard candy mass and at least a flavoring agent in proportions of 0.01 to 2.0%. The oral lozenges can contain various other substances. An oral lozenge preparation suitable as a carrier according to the invention is a hard candy mass with a flavor content of 0.05 to 1.5%. The hard candy mass is a solidified solution of amorphous sugar and can generally be formed from sugar solutions that are at high temperature are boiled down to such an extent that practically all of the water has been removed. Flavors and anti-plaque active ingredients are expediently added before boiling. The flavorings mentioned above in connection with dentifrices are also suitable for oral lozenges.

When processing preparations with anti-plaque active ingredients according to the invention for the production of oral and / or dental care products the amount of active ingredient introduced into the agent should be such that per application of the agent at least 0.001 g of antiplaque active ingredient is present. For dental care or dentifrice, the normal application amount is about 1 to 4 g and accordingly the dentifrice or dentifrice should be at least about 0.03%, preferably contain about 0.1 to about 2%, in particular about 0.5 to about 1.5%, antiplaque active ingredient. For mouth rinsing agent is the typical amount used per application is about 10 to about 20 g and a mouthwash should therefore be at least 0.01%, preferably about 0.5 to about 1.5% and in particular about 0.1 to about 1.0%, antiplaque active ingredient.

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The typical application amount for chewing gum and oral lozenges is about 1 to about 4 g _r and the antiplaque active ingredient content of chewing gum or oral lozenges should therefore be at least about 0.03%, preferably about 0.1 to about. 2%, in particular about 0.5 to about 1.5%.

In general, the oral and / or dental care products should contain about 0.01 to about 2.5% antiplaque active ingredient.

Oral and / or dental care products according to the invention can be desired tenf all also contain additional dental hygiene or therapeutically effective substances that can be used in the Oral cavity, such as anti-caries agents, e.g. water-soluble fluorides such as sodium fluoride or tin (II) fluoride, as well as anti-tartar agents, like trisodium ethane-l-hydroxy-l, l-diphosphonate.

Although the new bis-biduanide compounds of the present invention stain teeth much less than chlorhexidine, they are not entirely devoid of staining ability, and it is therefore often desirable to incorporate certain chelating agents into the compositions of the present invention which are useful in combating the general tendency of bis-biguanide to stain teeth. Antiplaque active ingredients as well as the tendency to stain the teeth due to natural causes, such as contact with certain foods and drinks, are suitable. Such chelating agents are described in _{US Pat. No. 3,937 "807 3} of DT-OS 2,534,887 (US Ser. No. ⁺⁾ . Examples of suitable chelating agents for this purpose are nitrate acetic acid, ethylenediamine diacetic acid, kojic acid, maltol, ethyl maltol, calcium dihydrogen ethylenediamine tetraacetate and di-N-substituted ethylenediaminediacetic acids, in which the substituents can be ethyl or 2-hydroxyethyl groups.The pharmacologically acceptable, water-soluble salts of these chelating agents are particularly good

584 30 ¹ O and the German patent application P (U.S. Ser.

No 652 692) 709807/1 159

useful, e.g. the sodium, potassium and ammonium salts. If a chelating agent is used, the agent should be sufficient Amount of chelating agent contained in such a way that a certain excess of chelating agent is present over that amount that reacts or will react with the bis-biguanide present. The concentration of such an excess of chelating agent it is generally from about 0.01% to about 1.25% based on the weight of the composition. Generally two respond Mole of chelating agent with one mole of the bis-biguanide compound.

The following examples are intended to explain the invention further,

example 1

A toothpaste of the following composition is made:

Component parts by weight

Sorbitol (70% solution) 20.00

Sodium saccharin 0.21

"Veegum" (colloidal magnesium

aluminum silicate) 0.40

precipitated urea / formaldehyde condensate (Abrasive) 30.00

Flavor 1.00

Sodium carboxymethyl cellulose 1.30

Glycerin 10.00

1,2-bis (N -m-trifluoromethylphenyl-N biguanido) ethane gluconate 0.70

Polyoxyäthylensorbita.n (20) -mono-

isostearate 1.50

distilled water remainder

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This toothpaste is effective in normal use by slowing down the build-up of dental plaque and making one considerably causes less staining on the teeth than chlorhexidine.

Example 2

A mouthwash according to the invention is composed as follows :

Component parts by weight

Ethyl alcohol (95% in water) 12.00

Cetyl pyridinium chloride 0.10

Polyoxyethylene (20) -sorbitan-

monooleate 0.12

Sodium hydroxide (10% in water) 0.02

Sodium saccharin 0.055

Flavor 0.16

l.-2-bis (N-lu-trifluorir.ethylphenyl-N biguanido) -ethane dihydrochloride 0.20

Color 0.50

Sorbitol (70% in water) 12.00

distilled water remainder

When used to rinse the mouth in the usual manner, this product is effective in slowing the build-up of dental plaque and causes a significantly lower degree of staining of the teeth than chlorhexidine.

Example 3

According to the invention, chewing gum is composed of the following components:

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6.40 2633651 component 9.60 Parts by weight Chewing gum base 3.20 21.30 Estergumini 2.10 Coumarone resin dry chew
school latex Paraffin wax
(Mp 82 ° C) sugar 58.45 Corn Syrup (45 ° Baume) 18.20

Flavor 1.05

1,2-Bis (N ⁵ -m-trifluoroxnethylphenyl-N ¹ -biguanido) -ethane diacetate 1.00

When chewing this gum in the normal way, the formation of dental plaque is delayed and there is considerably less staining of the teeth causes than with chlorhexidine.

Example 4

If in the above examples the 1,2-bis (N -m- .trifluoromethylphenyl-N -biguanido) ethane salts are replaced by the digluconate or diacetate salts of the following compounds you get similar results by increasing the anti-plaque efficacy is achieved with significantly less tooth staining than is the case with the use of chlorhexidine:

1,4-bis (N -m-trifluoromethylphenyl-N-biguanido) -butane, 1,2-bis (N -m-trifluoromethylbenzyl-N-biguanido) ethane,

5 5

1,2-bis (N -m-trifluoromethylphenyl-N -hexyl-N-biguanido) ethane,

1,2-bis (N ⁵ -m-trifluoromethylphenyl-N -2-phenethyl-N-biguanido) -

ethane,

-m-trif! biguanido) -butane,

• m-trif] ethane,

• m-trif: ethane,

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1,4-bis (N ⁵ -m-trifluoromethylphenyl-N ⁵ -ethyl-N ¹ -methyl-N ¹ -biguanido) -butane,

1,2-bis (N -m-trifluoromethylbenzyl-N -methyl-N-biguanido) ethane,

5 5

1,2-bis (N -m-trifluoromethylphenyl-N -phenethyl-N-biguanido) -

1,2-bis (N -ρ-trifluoromethylphenyl-N-biguanido) -ethane, 1,2-BiS (N -ο-trifluorraethylphenyl-N-biguanido) -ethane, Bis- (N ~ m-tri fluorine thy lphenyl-N-biguanido) methane.

709807/1159

Claims (20)

PATENT CLAIMS 1 / bis-biguanido compounds of the general formula R NH NH RR 'NH NH R ¹ I Il Il I ~ I ^ Ii Il I -NC-NH-C - N- (CH.) -N - C-NH-C - N- (X ¹ ) r (\ /) 2 η ζ '\\ ι // "3 (" ¹ T * ¹ in v / elcher η denotes a number from 1 to 4 inclusive, X and X ¹ each represent an alkylene radical containing 1 to 3 carbon atoms, ζ and z ^{1 are} zero or one, R and R ^{1 are} each hydrogen atoms, alkyl radicals with 1 to about 12 carbon atoms or aralkyl radicals with 7 to about 12 carbon atoms and R_ and R ₂ ^{1 are} each hydrogen atoms or alkyl radicals with 1 to 2 carbon atoms, as well as the pharmacologically permissible salts of these compounds. 2. Compounds according to claim 1 in the form of the water-soluble . chen salts. 3. Compounds according to claim 2 in the form of the dihydrochloride, Diacetate or digluconate salts. 4. Compounds according to claim 1, in which η is 2, ζ and z ^{1 are} each zero and R, R ¹ , R ₀ and R ₉ ¹ each represent hydrogen atoms. 5. Compounds according to claim 4, in which the trifluoromethyl groups stand in meta-pitch. 6. Compounds according to claim 4 in the form of pharmacological permissible, water-soluble salts. 7. Compounds according to claim 5 in the form of pharmacological permissible, water-soluble salts. 709807/1159 8. Compounds according to claim 7 in the form of the dihydrochloride, Diacetate or digluconate salts. 9. Oral and / or dental care products, characterized in that it is a carrier for use in the oral cavity and about 0.01 to about 2.5% antiplaque active ingredient of the formula R NH NH R ₂ R ₂ ¹ NH NH R ¹ (X) -NC-NH-C - N- (CH.) -N - C-NII-C - N- (X ¹ ) r (\ Z Δ Ti Z ¹ \\ in which η denotes a number from 1 to 4 inclusive, X and X ¹ each represent an alkylene radical containing 1 to 3 carbon atoms, ζ and z ^{1 are} zero or one, R and R ^{1 are} each X hydrogen atoms, alkyl radicals with 1 to mean about 12 carbon atoms or aralkyl radicals with 7 to about 12 carbon atoms and R- and -R- ^{1 are} each hydrogen atoms or alkyl radicals with 1 to 2 carbon atoms, or contains pharmacologically acceptable salts thereof. . 10. Agent according to claim 9, characterized in that it contains the antiplaque active ingredient in the form of a water-soluble, contains pharmacologically acceptable salt. 11. Means according to claim 10, characterized in that it contains the antiplaque active ingredient in the form of dihydrochloride, diacetate or contains digluconate salt. 12. Means according to claim 9, characterized in that η is 2, ζ and z ^{1 are} each zero, and R, R ¹ , R ₂ and R 'each represent hydrogen atoms. 13. Agent according to claim 12, characterized in that the trxfluoromethyl groups of the antiplaque active ingredient are in meta position stand. 709807/115 9 14 : Agent according to claim 12, characterized in that the antiplaque active ingredient is a pharmacologically acceptable, water-soluble salt. 15. Means according to claim 13, characterized in that the antiplaque active ingredient is a pharmacologically acceptable, water-soluble one Salt is. 16. Means according to claim 15, characterized in that the salt is the dihydrochloride, diacetate or digluconate salt. 17. Composition according to claim 16, characterized in that it contains the antiplaque active ingredient in proportions of about 0.05%
contains about 1.2%. 18. Agent according to claim 16 in the form of a dentifrice, characterized in that it contains the antiplaque active ingredient in proportions of about 0.1% to about 2.0% and as a further
Component contains about 0.5% to about 95% abrasive or abrasive agent. 19. Composition according to claim 16 in the form of a mouthwash, characterized in that it contains the antiplaque active ingredient Proportions from about 0.5% to about 1.5% and also as additional components (A) about 5% to about 40% ethyl alcohol, (B) zero to about 20% humectant,
.- (C) zero to about 2% foaming agent, (D) zero to about 0.5% sweetener, (E) about 0.05% to about 0.3% flavor and (F) Contains water as the remainder. 709807/115 9 20. Means according to one of the claims 9 to 19, characterized in that that there is additionally, based on the weight of the agent, about 0.01% to about 1.25% chelating agent in excess contains about the amount of chelating agent reacting with the bis-biguanide compound, the chelating agent nitrilotriacetic acid, Ethylenediamine diacetic acid, kojic acid, maltol, ethyl maltol, calcium dihydrogen ethylenediamine tetraacetate, a di-N-substituted ethylenediaminediacetic acid, whose substituents are ethyl or 2-hydroxyethyl groups, or a pharmacologically acceptable, water-soluble salt of one such chelating agent is. For: The Procter & Gamble Company Cincinnati, Ohio, V.St.A. Jr. H. J. Wolff Attorney at Law 709807/1159