N-alkyldiethanolamine hydrofluorides and oral hygiene...

Details N-alkyldiethanolamine hydrofluorides and oral hygiene... N-alkyldiethanolamine hydrofluorides and oral hygiene...

1999-08-04

2002-10-15

Gitomer, Ralph (Department: 1627)

Drug, bio-affecting and body treating compositions

Dentifrices

C424S052000, C424S054000, C433S217100

Reexamination Certificate

active

06464962

ABSTRACT:

The present invention relates to amine hydrofluorides and mixtures of these amine hydrofluorides, and to a process for the preparation of these amine hydrofluorides and their use in oral hygiene compositions.
It is known that oral hygiene compositions, by their cleaning action, make a contribution to the hygiene of the oral cavity and thus to the preservation of the health of teeth and gums. The cleaning action of these oral hygiene compositions is customarily supplemented by admixture of active compounds which prevent or control pathological symptoms in the oral cavity, in particular also the formation of bacterial films on the teeth (plaque). These films consist of polysaccharides, primarily of dextrans. In addition to the low-molecular weight sugars, these polysaccharides form a source of nutrition for the plaque bacteria (mainly streptococci and lactobacillaceae). The plaque bacteria gradually break down the polysaccharides to form acidic degradation products (e.g. pyruvic acid, lactic acid etc.). The pH decrease resulting therefrom brings about the degradation of the tooth enamel known as caries.
It has therefore already been attempted to take steps against the formation of pathological symptoms in the oral cavity using various oral hygiene compositions comprising antibacterially active substances (e.g. toothpastes, rinsing solutions or dental gels). Active compounds already known from the prior art are N-octadeca-9-enylamine hydrofluoride (international non-proprietary name “dectaflur”) and in particular N′-octadecyl-N′,N,N-tris(2-hydroxyethyl)-1,3-propanediamine dihydrofluoride (international non-proprietary name “olaflur”). On oral use of the hygiene composition, these active compounds form a thin hydrophobic film on the tooth enamel, the amine hydrofluoride groups coming into contact with the tooth enamel. Thus on the one hand the tooth enamel becomes more resistant to acid attacks on account of the CaF
2
covering layer formed, on the other hand the long-chain hydrocarbon residues form a hydrophobic layer which prevents the formation of deposits and the attack of the acidic degradation products on the tooth enamel.
The synthesis of olaflur starts from bovine tallow, a fat having a high stearic acid content. The ester groups are hydrolysed, the free fatty acids are converted into the corresponding amides using ammonia and these are dehydrated to the nitrites. Catalytic reduction thereof yields a mixture of primary fatty amines with the main constituent octadecylamine. Reaction with acrylonitrile and catalytic re-reduction affords N-octadecyl-1,3-propanediamine, which is hydroxyethylated using ethylene oxide. Amounts of by-products are formed here, as the amino groups are in some cases under- or over-substituted. The hydroxyethyl groups introduced can also be etherified by means of further ethylene oxide. The subsequent double hydrofluoridation yields the final product olaflur in technical purity, in which N′-octadecyl-N′,N,N-tris(2-hydroxyethyl)-1,3-propanediamine dihydrofluoride occurs as the main component. The purification of the by-products is dispensed with for cost reasons.
The presence of these by-products was until now not considered to be inconvenient, since in relation to the film formation on the enamel they are of secondary importance. However, it has to be taken into account that in the course of the global tightening of the official approval procedures for pharmaceutical active compounds in future the marketing authorizations for contaminated active compounds will be more difficult to obtain.
The present invention is based on the object of providing active compounds which have an activity comparable with olaflur, but contain less by-products and are simpler to prepare.
The object set is achieved according to the invention by amine hydrofluorides of the general formula (I):
R—N(CH
2
CH
2
OH)
2
.HF   (I)
where R is a straight-chain hydrocarbon residue having 10 to 20 carbon atoms.
It has namely been found that these amine hydrofluorides and mixtures of two or more thereof have an antibacterial activity which is very similar to that of the N′-octadecyl-N′,N,N-tris(2-hydroxyethyl)-1,3-propanediamine dihydrofluoride from the already-known olaflur. The antibacterial action manifests itself in the inhibition of the growth of a multiplicity of micro-organisms, for instance of
Aspergillus niger, Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis
and
Enterobacter cloacae.
The amine hydrofluorides according to the invention in particular inhibit the sugar degradation in acid-producing plaque bacteria and, owing to the formation of a hydrophobic film, increase the acid resistance of the hard tooth substance and thus have caries-prophylactic action. They also favour the remineralization of initial carious lesions.
The amine hydrofluorides according to the invention contain straight-chain (i.e. unbranched) hydrocarbon residues. They can have hydrocarbon residues with both an even- and odd-numbered chain length. Residues having an even-numbered chain length are preferred with regard to physiological acceptability. The residues can preferably be fully saturated or mono-, di- or polyunsaturated. Examples of saturated hydrocarbon residues having an even-numbered chain length are decyl, dodecyl (lauryl), tetradecyl (myristyl), hexadecyl (cetyl, palmityl), octadecyl (stearyl) and eicosanyl. Examples of unsaturated residues having an even-numbered chain length are 9-cis-octadecenyl (oleyl), 9-trans-octadecenyl (elaidyl), cis,cis-9,12-octadecadienyl (linolyl), cis,cis,cis-9,12,15-octadecatrienyl (linolenyl) or 9-cis-eicosaenyl (gadolyl). Lauryl, myristyl, cetyl, oleyl and stearyl residues are preferred.
The amine hydrofluorides are prepared according to the invention by reacting an amine of the general formula (II):
R—N(CH
2
CH
2
OH)
2
  (II)
in which R is a hydrocarbon residue having 10 to 20 carbon atoms, with hydrogen fluoride. The reaction can be carried out in all solvents which have an adequate solubility for the free amine of the formula (II) and are not attacked by hydrogen fluoride. Examples of suitable solvents are C
1
- to C
4
-alcohols and dimethyl sulfoxide: ethanol is particularly preferred. The addition of the hydrogen fluoride as an aqueous solution, i.e. as hydrofluoric acid , is preferred. The hydrogen fluoride is preferably added in an amount from 1 to 5, particularly preferably from 1.0 to 1.1, equivalents, based on the amine. The temperature of the reaction is not critical and can in general be between −10 and +100° C., whereby the upper limit may be given by the boiling point of the solvent, or the lower limit by the melting point of the solvent. The preferred temperature of the reaction is between 25° C. and 40° C. After the completion of the addition of the hydrogen fluoride, the reaction mixture can be evaporated and dried, by means of which the amine hydrofluoride according to the invention is obtained. A possible small hydrogen fluoride loss during the evaporation and drying can be compensated by subsequent addition of a corresponding amount of hydrofluoric acid in the preparation of the formulations according to the invention.
The amine of the formula (II) can be prepared in a manner which is known or known per se by hydroxyethylation of a primary amine R—NH
2
, in which R has the above meaning, with ethylene oxide (oxirane), the ethoxylation taking place virtually quantitatively only on the nitrogen atom.
The primary amine R—NH
2
can be obtained in a known manner from a fatty acid of the formula R—COOH, in which R has the above meaning, by means of the synthesis steps amide formation/dehydration/catalytic reduction, as are also used in the synthesis of the already-known olaflur. Suitable fatty acids or fatty acid mixtures of the formula R—COOH and suitable amines or amine mixtures of the formula R—NH
2
are known and in some cases obtainable commercially.
According to a further variant, the amine of the formula (II) ca

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